PEPTIDE INHIBITORS OF A PHOSPHOTYROSINE-BINDING DOMAIN CONTAINING PROTEIN

Abstract: A peptide of the formula (I): X<1>-A<1>-A<2>-X<2>-Asn-X<3>-X<4>-P.Tyr-X<5>-X<6>-X<7->X<8>, wherein X<1> represents Lys, Arg, His, Ser, Thr, Tyr, Asn, Leu, Val or Glu, A<1> represents Trp, Leu, Ala, Ser, Ile, Glu, Met, Gly, Cys, Phe, Pro or Val, and A<2> represents Ala, Val, Leu, Ile, Ser, Met, Phe, Gly, Cys, Trp or Pro, X<2> represents Glu, Asn, Tyr, Thr, Ser, Asp or Ile, X<3> represents Pro, Met, Trp, Phe, Ala, Lys, Val, Leu, Ile, Gly or Cys, X<4> represents Leu, Ala, Glu, Gln, Asp, Asn, Tyr, Thr or Ser, X<5> represents Phe, Trp, Pro, Leu, Ala, Val, Ile, Gly, Cys, Met, Arg or Ser, X<6> represents Ser, Thr, Tyr, Asn, Glu, Met, Ala, Leu, Val or Gly, X<7> represents Asp, Glu, Ala, Val, Leu, Ile, Gly, Cys, Phe, Trp, Met, Pro, Ser or Asn and X<8> which may be present or absent represents Phe, Trp, Pro, Leu, Ala, Val, Ile, Gly, Cys, Met, Asp, Ser or Arg which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site, and truncations and analogues of the peptide.

Description: PEPTIDE INHIBITORS OF A PHOSPHOTYROSINE-BINDING DOMAIN CONTAINING PROTEIN FIELD OF THE INVENTION The invention relates to peptides which interfere with the interaction of a phosphotyrosine-binding (PTB) domain containing protein with a PTB domain binding site; and, uses of the peptides. BACKGROUND OF THE INVENTION She is a member of a group of proteins that are collectively known as adaptor proteins. These adaptors, which are composed of protein-protein interaction domains such as the Src-homology 2 (SIC) and Src-homology 3 (SH3) domains, mediate protein-protein interactions that are important for signal transduction downstream of growth factor and cytokine receptors (Pawson, 1995). She has been shown to bind to a wide variety of activated growth factor and cytokine receptors. She was cloned from a human cDNA library in a screen for SH2 domain-containing proteins (Pelicci et al., 1992); She homologs in mouse (mShc) and drosophila (dShc) have also been cloned (Lai et al, 1995). Three proteins are encoded by the she gene that differ from each other only in their amino- terminus (Lai et al, 1995; Pelicci et al, 1992). Overexpression of She results in cellular transformation of NTH3T3 fibroblasts and Ras-dependent neurite outgrowth of PC 12 cells, suggesting that She plays an important role in signal transduction leading to DNA synthesis and cell division or differentiation (Pelicci et al, 1992; Rozakis-Adcock et al, 1992). She contains an amino-terminal phosphotyrosine-binding (PTB) domain, a central Pro-rich region that contains the principal tyrosine phosphorylation site at Tyr 317, and an SH2 domain at its carboxy-terminus. The PTB domain, which is highly conserved in She- related proteins, was recently identified based on its ability to bind to phosphotyrosine- containing proteins (Blaikie et al, 1994; Kavanaugh and Williams, 1994; van der Geer et al, 1995). It recognizes phosphotyrosine present within the sequence Asn-Pro-X-P.Tyr and differs from SH2 domains that recognize phosphotyrosine in the context of carboxy- terminal residues (Kavanaugh et al, 1995; van der Geer et al, 1995). The She SH2 domain recognizes phosphotyrosine within the sequence P.Tyr-Glu/Leu/Ile/Tyr-X-Leu/Ile/ Met (Songyang et al, 1994). She becomes phosphorylated on tyrosine following stimulation with a wide variety of growth factors and cytokines (Burns et al, 1993; Crowe et al, 1994; Cutler et al, 1993; Lanfrancone et al, 1995; Pelicci etal, 1992; Pronk et α/., 1993; Ravichandran et al, 1993; Segatto et al, 1993; Yokote et al, 1994). Tyrosine phosphorylation of She is essential for its interaction with the Grb2-Sos complex, which may provide a mechanism for Ras activation (Buday and Downward, 1993; Crowe et al, 1994; Egan et al, 1993; Gale et al, 1993; Li et al, 1993; Rozakis-Adcock et al, 1993; Rozakis-Adcock et al, 1992; Salcini et al, 1994). She has also been shown to bind physically to activated growth factor and cytokine receptors. Several growth factor receptors that had previously been shown to bind to She upon activation contain tyrosine phosphorylation sites present within the sequence Asn-Pro-X-P.Tyr, consistent with the notion that it is the PTB domain that mediates She's interaction with these proteins (Campbell et al, 1994; van der Geer and Pawson, 1995). Furthermore, the She PTB domain has been shown to bind to the activated nerve growth factor (NGF) receptor, the activated epidermal growth factor (EGF) receptor, polyoma middle T antigen, and to a 145 kDa protein that becomes phosphorylated on tyrosine in PDGF stimulated cells (Blaikie et al, 1994; Kavanaugh and Williams, 1994; van der Geer et al, 1995). The NGF receptor contains a single She-binding site at Tyr 490 that is present within a Asn-Pro-X-Tyr motif (Obermeier et al, 1994; Stephens et al, 1994). NGF receptors that have been mutated at Tyr 490 lack the ability to interact with She in vivo or with the PTB domain in vitro (Stephens et al, 1994). Phosphotyrosine-containing peptides based on the She binding site in middle T antigen, which is also present within an Asn-Pro- X-P.Tyr motif, compete with the NGF and EGF receptors for binding to the PTB domain (van der Geer et al, 1995). SUMMARY OF THE INVENTION The present inventors have identified the residues within the Asn-Pro-X-P Tyr motif of phosphotyrosine-containing proteins (e.g. growth activated growth factors and cytokine receptors) that mediate the binding of the proteins to signalling proteins containing PTB domains. In particular, the present inventors found that the Asn and the phosphotyrosine residues within the Asn-Pro-X-P.Tyr motif of the phosphotyrosine-containing proteins mediate their binding to the PTB domain of She. The present inventors also found that an aliphatic residue that is five or six residues amino-terminal to the phosphotyrosine is required for binding. This aliphatic residue is missing from the insulin receptor autophosphorylation site which is unable to form a stable complex with She. The present inventors also analyzed the She PTB domain by in vitro mutagenesis and an evolutionarily conserved Arg residue was identified that is important for PTB binding to its ligands. Broadly stated the present invention relates to a peptide of the formula I X 1 - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X'-X 8 I wherein X 1 represents Lys, Arg, His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, A 1 represents Trp, Leu, Ala, Ser, He, Glu, Met, Gly, Cys, Phe, Pro, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, Phe, Gly, Cys, Tφ, or Pro, X 2 represents Glu, Asn, Tyr, Thr, Ser, Asp, or He, X 3 represents Pro, Met, Tφ, Phe, Ala, Lys, Val, Leu, He, Gly, or Cys, X 4 represents Leu, Ala, Glu, Gin, Asp, Asn, Tyr, Thr, or Ser, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Arg or Ser, X 6 represents Ser, Thr, Tyr, Asn, Glu, Met, Ala, Leu, Val, or Gly, X 7 represents Asp, Glu, Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, Ser, or Asn, and X 8 which may be present or absent represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Asp, Ser, or Arg, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In an embodiment of the present invention a peptide of the formula I is provided. X 1 - A 1 - A 2 - X - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 - X 8 I wherein X 1 represents His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, X 2 represents Glu, Ser, Asp, or He, X 3 represents Pro or Lys, X 4 represents Leu, Ala, Glu, Gin, Asn, or Thr, X 5 represents Phe, Leu, He, Gly, Arg, or Ser, X 6 represents Ser, Thr, Met, Ala, Leu, Val, or Gly, X 7 represents Asp, Ala, Val, Leu, Met, Ser, or Asn, X 8 which may be present or absent, represents Leu, Ala, Gly, Asp, Ser, or Arg, A 1 represents Tφ, Leu, Ala, Ser, He, Glu, Met, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, or Phe, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In another embodiment of the invention a peptide of the formula Ia is provided X 1 - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 Ia wherein X 1 represents Lys, Arg, His, preferably His, X 2 represents Glu, Asn, Tyr, Thr, Ser, preferably Glu, X 3 represents Pro, Met, Trp, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Gin, Asp, Asn, Tyr, Thr, Ser, preferably Gin, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, preferably Phe, X 6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Asp, Glu, preferably Asp, and one of A 1 and A 2 represents He and the other of A 1 and A 2 represents He or Ala, preferably A 1 represents Ala and A 2 represents He, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In still another embodiment of the invention a peptide of the formula Ia is provided X 1 - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 Ia wherein X 1 represents Ser, Thr, Tyr, Asn or Glu, preferably Tyr, X 2 represents Glu, Asn, Tyr, Thr, Ser, preferably Ser, X 3 represents Pro, Met, Tφ, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Glu, Asp, preferably Glu, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met preferably Leu, X 6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, preferably Ala, and one of A 1 and A 2 represents He and the other of A 1 and A 2 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met or Pro, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. The invention also relates to truncations and analogs of the peptides of the invention. The invention also relates to the use of a peptide of the formula I or Ia to interfere with the interaction of a PTB domain containing protein with a PTB domain binding site; and, pharmaceutical compositions for inhibiting the interaction of a PTB domain containing protein with a PTB domain binding site. Further, the invention relates to a method of modulating the interaction of a PTB domain containing protein with a PTB domain binding site comprising changing the amino acid Arg at position 175 in the PTB domain containing protein. The invention still further relates to a method for modulating the interaction of an insulin receptor with insulin receptor substrate 1 (IRS-1) or She comprising incoφorating a large aliphatic amino acid at amino acids -5 or -6 amino terminal to the P.Tyr in the motif Asn-Pro-X-P.Tyr in the PTB domain of the insulin receptor. Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. DESCRIPTION OF THE DRAWINGS The invention will be better understood with reference to the drawings in which: Figure 1 A is an immunoblot showing P.Tyr-containing proteins bound to GST (lane 2) and GST She PTB (lanes 1, 3-6) fusion proteins immobilized on glutathione-agarose after incubation with lysates from control (lane 1) and NGF -stimulated (lanes 2-7) cells in the absence (lane 1-3) and presence of Wt (lane 4) and mutant (lanes 5 and 6) competing P.Tyr containing peptides, based on the sequence around Tyr 490 the She PTB domain binding site in the NGF receptor; Figure IB is the immunoblot shown in Figure IA stripped and reprobed with an antiserum raised against the NGF receptor; Figure 2 is a graph showing the results of surface plasmon resonance technology testing the ability of Wt and mutant phosphopeptides, based on the sequence around Tyr 490 the She-binding site in the NGF receptor to compete for binding of the GST-Shc PTB domain fusion protein to the immobilized polyoma middle T antigen peptide; Figure 3 is a schematic diagram showing the presence of an Asn-Pro-X-P.Tyr motif in the juxta membrane domains of the NGF and insulin receptors; Figure 4A is an immunoblot showing anti-She immunoprecipitates (lanes 1, 2, 5, 6, 9, and 10) from control (lanes 1, 5, and 9) and growth factor-stimulated (lanes 2, 6, and 10) NLH3T3 fibroblasts expressing Wt (lanes 1 and 2; NGFR) or Phe 490 mutant (lanes 5 and 6; F490NGFR) NGF receptors, or CHO cells expressing Wt insulin receptors (lanes 9 and 10; IR) analyzed by anti-P.Tyr immunoblotting; anti-NGF receptor (lanes 3, 4, 7, and 8) and anti-insulin receptor immuno-precipitates (lanes 11 and 12) from control (lanes 3, 7, and 11) and growth factor stimulated (lanes 4, 8, and 12) were analyzed in parallel; Figure 4B is an immunoblot showing Wt (lanes 1 and 2) and Phe 490 mutant (5 and 6) NGF receptors present in lysates from control (lanes 1 and 5) and NGF-stimulated (lanes 2 and 6) cells expressing Wt (NGFR) or Phe 490 mutant (F490NGFR) and insulin receptors (LR) present in lysates from control (lane 9) and insulin-stimulated (lane 10) cells incubated with GST-Shc PTB fusion proteins bound to glutathione-agarose, bound proteins were analyzed by anti-P.Tyr blotting; Figure 5A is an immunoblot showing GST-Shc PTB domain fusion proteins bound to glutathione-agarose after incubation with activated NGF receptors present in lysates of NGF-stimulated cells in the absence (lane 1) or presence (lanes 2-7) of 2 μM competing Wt and mutant phosphotyrosine containing peptides based on the sequence around Tyr 490, the She PTB domain binding site in the NGF receptor (lanes 2-5) or Tyr 960 an autophosphorylation site present within an Asn-Pro-X-P.Tyr motif in the insulin receptor (lanes 6 and 7); Figure 5B is a graph showing the results of testing phosphopeptides based on the sequence around Tyr 490, the She-binding site in the NGF receptor (H-I-I-E-N-P-Q-p. Y-F- S-D; (•) or Tyr. 960 in the insulin receptor (Y-A-S-S-N-P-E-p.Y-L-S-A; (O) and substitutions at position -5 and -6 with respect to the P.Tyr in the NGF receptor peptides (H- A-S-E-N-P-Q-p.Y-F-S-D;(«)) and the insulin receptor peptide (Y-A-I-S-N-P-E-p.Y-L-S-A; (A) for their ability to compete for the binding of the GST-Shc PTB domain to the immobilized polyoma middle T antigen peptide (L-S-L-L-S-N-P-T-p.Y-S-V-M-R-S-K); Figure 6A is an immunoblot showing GST fusion proteins containing Wt (lanes 1 and 2) or mutant (lanes 3-11) She PTB domains after incubation with NGF receptors present in lysates of control (lane 1) and NGF-stimulated cells (lanes 2-11), bound proteins were analyzed by anti-P.Tyr blotting, Figure 6B is an immunoblot showing human EGF receptors bound to GST fusion proteins containing Wt (lanes 1 and 2) or Met 175 (lane 3) and Lys 175 (lane 4) mutant human She PTB domains in lysates from control (lane 1) or EGF -stimulated cells (lanes 2- 4) analyzed by anti-P.Tyr blotting, and in parallel GST (lane 8) and GST fusion proteins containing Wt (lane 7) or an Ala 151 mutant (lane 9) drosophila She PTB domain bound to glutathione-agarose, incubated with fly lysates containing activated Torso-DER chimeric proteins that contain the cytoplasmic domain of DER; bound proteins were detected by anti- P.Tyr blotting; Figure 7 shows the amino acid sequences of PTB binding domains of mammalian and Drosophila She homologues; Figure 8 are immunoblots showing competitive inhibition of EGF receptor binding to GST-ShcB analyzed by anti-phospho-tyrosine antibody; Figure 9 is an immunoblot showing competitive inhibition of EGF receptor binding to GST-ShcB analyzed by anti-phospho-tyrosine antibody; Figure 10 are immunoblots showing a dose-response analysis in a competitive inhibition assay of EGF receptor binding to GST-ShcB analyzed by anti-phospho-tyrosine antibody; Figure 11 are bar graphs showing proliferation of HER14 cells treated with peptides of the invention; Figure 12 is a bar graph showing proliferation of HER14 cells treated with peptides of the invention; Figure 13 is a bar graph showing proliferation of HER14 cells treated with cyclic peptides of the invention; Figure 14 are bar graphs showing proliferation of SupM2 cells treated with peptides of the invention; Figure 15 are immunoblots showing MAPK activation on PC 12 cells treated with peptides of the invention; and Figure 16 are immunoblots showing activated MAPK on PC 12 cells treated with peptides of the invention. DETAILED DESCRIPTION OF THE INVENTION The following standard abbreviations for the amino acid residues are used throughout the specification: A, Ala - alanine; C, Cys - cysteine; D, Asp- aspartic acid; E, Glu - glutamic acid; F, Phe - phenylalanine; G, Gly - glycine; H, His - histidine; I, He - isoleucine; K, Lys - lysine; L, Leu - leucine; M, Met - methionine; N, Asn - asparagine; P, Pro - proline; Q, Gin - glutamine; R, Arg - arginine; S, Ser - serine; T, Thr - threonine; V, Val - valine; W, Tφ- tryptophan; Y, Tyr - tyrosine; and p.Y., P.Tyr - phosphotyrosine. As mentioned previously, the present invention relates to a peptide of the formula I X 1 - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 -X 8 I wherein X 1 represents Lys, Arg, His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, A 1 represents Tφ, Leu, Ala, Ser, He, Glu, Met, Gly, Cys, Phe, Pro, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, Phe, Gly, Cys, Tφ, or Pro, X 2 represents Glu, Asn, Tyr, Thr, Ser, Asp, or He, X 3 represents Pro, Met, Tφ, Phe, Ala, Lys, Val, Leu, He, Gly, or Cys, X 4 represents Leu, Ala, Glu, Gin, Asp, Asn, Tyr, Thr, or Ser, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Arg or Ser, X 6 represents Ser, Thr, Tyr, Asn, Glu, Met, Ala, Leu, Val, or Gly, X 7 represents Asp, Glu, Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, Ser, or Asn, and X 8 which may be present or absent represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Asp, Ser, or Arg, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In an embodiment of the present invention a peptide of the formula I is provided: X 1 - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7" X 8 I wherein X 1 represents His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, X 2 represents Glu, Ser, Asp, or He, X 3 represents Pro or Lys, X 4 represents Leu, Ala, Glu, Gin, Asn, or Thr, X 5 represents Phe, Leu, He, Gly, Arg, or Ser, X 6 represents Ser, Thr, Met, Ala, Leu, Val, or Gly, X 7 represents Asp, Ala, Val, Leu, Met, Ser, or Asn, X 8 which may be present or absent, represents Leu, Ala, Gly, Asp, Ser, or Arg, A 1 represents Tφ, Leu, Ala, Ser, He, Glu, Met, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, or Phe, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In another embodiment of the invention a peptide of the formula Ia is provided X' - A 1 - A 2 - X 2 - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 Ia wherein X 1 represents Lys, Arg, His, preferably His, X 2 represents Glu, Asn, Tyr, Thr, Ser, preferably Glu, X 3 represents Pro, Met, Trp, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Gin, Asp, Asn, Tyr, Thr, Ser, preferably Gin, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, preferably Phe, X 6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Asp, Glu, preferably Asp, and one of A 1 and A 2 represents He and the other of A 1 and A 2 represents He or Ala, preferably A 1 represents Ala and A 2 represents He, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. In still another embodiment of the invention a peptide of the formula Ia is provided X 1 - A 1 - A 2 - X - Asn - X 3 - X 4 - P.Tyr - X 5 - X 6 - X 7 Ia wherein X 1 represents Ser, Thr, Tyr, Asn or Glu, preferably Tyr, X 2 represents Glu, Asn, Tyr, Thr, Ser, preferably Ser, X 3 represents Pro, Met, Tφ, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Glu, Asp, preferably Glu, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met preferably Leu, X 6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, preferably Ala, and one of A 1 and A 2 represents He and the other of A 1 and A 2 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met or Pro, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site Preferred peptides of the invention include the following His-Ile-Ile-Glu-Asn-Pro- Gln-P Tyr-Phe-Ser-Asp, His-Ala-Ile-Glu-Asn-Pro-Gln-P Tyr-Phe-Ser-Asp, His-Ile-Ala- Glu-Asn-Pro-Gln-P Tyr-Phe-Ser-Asp, Ile-Ile-Glu-Asn-Pro-Gln-P Tyr-Phe-Ser-Asp-Ala, Tyr-Ala-Ile-Ser-Asn-Pro-Glu-P Tyr-Leu-Ser-Ala, Thr-Tφ-Ile-Glu-Asn-Lys-Leu-P Tyr- Gly-Met-Ser-Asp, Thr-Tφ-Ile-Glu-Asn-Lys-Leu-P Tyr-Gly-Thr-Ser-Asp, Leu-Leu-Leu- Ser-Asn-Pro-Ala-P Tyr -Arg-Leu-Leu-Leu, Tyr-Ala-Ser-Ser-Asn-Pro-Glu-P Tyr-Leu-Ser- Ala-Ser, Val-Ser-Val-Asp-Asn-Pro-Glu-P Tyr-Leu-Leu-Asn-Ala, Ser-Leu-Leu-Ser-Asn- Pro-Thr-P.Tyr-Ser-Val-Met-Arg, Asn-Glu-Met-Ile-Asn-Pro-Asn-P Tyr-Ile-Gly-Met-Gly, and Glu-Met-Phe-Glu-Asn-Pro-Leu-P Tyr-Gly-Ser-Val-Ser (SEQ ID NOS 1 -13 in the Sequence Listing) In addition to full-length peptides of the formula I, truncations of the peptides which inhibit interaction of PTB domain containing proteins with PTB domain binding sites are contemplated in the present invention Truncated peptides may comprise peptides of about 7 to 10 amino acid residues In an embodiment of the invention the truncated peptide has the sequence A 2 -X 2 -Asn-X 3 -X 4 -P Tyr or A 2 -X 2 -Asn-X 3 -X 4 -P Tyr-X 5 wherein A 2 , X 2 , X 3 , X 4 , and X 5 are as defined above In a preferred embodiment of the invention, the truncated peptide has the sequence Leu/Ile-X 2 -Asn-Pro-X 4 -P Tyr, wherein X 2 represents Glu, Ser, Asp, or He, and X 4 represents Leu, Ala, Glu, Gin, Asn, or Thr Examples of truncated peptides include Ile-Glu-Asn-Pro-Gln-P Tyr-Phe, Ile-Glu-Asn-Pro-Gln-P Tyr-Phe-Ser-Pro- Gly, Ala-Glu-Asn-Pro-Gln-P Tyr-Phe, Ile-Glu-Asn-Pro-Gln-P Tyr-Phe-Ser, Ile-Ser-Asn- Pro-Glu-P Tyr-Leu, Val-Leu-Ala-Asp-Asn-Pro-Ala-P Tyr-Arg-Ser-Ala (SEQ LD NOs 14 to 19 in the Sequence Listing) The truncated peptides may have an ammo group (-NH 2 ), a hydrophobic group (for example, carbobenzoxyl, dansyl, or T-butyloxycarbonyl), an acetyl group, a 9- fluorenylmethoxy-carbonyl (PMOC) group, or a macromolecule including but not limited to lipid-fatty acid conjugates, polyethylene glycol, or carbohydrates at the amino terminal end The truncated peptides may have a carboxyl group, an amido group, a T- butyloxycarbonyl group, or a macromolecule including but not limited to lipid-fatty acid conjugates, polyethylene glycol, or carbohydrates at the carboxy terminal end The peptides of the invention may also include analogs of the peptide of the Formula I, and/or truncations of the peptide, which may include, but are not limited to the peptide of the formula I containing one or more amino acid insertions, additions, or deletions, or both. Analogs of the peptide of the invention exhibit the activity characteristic of the peptide i.e. interference wim the interaction of a PTB domain containing protein with a PTB domain binding site, and may further possess additional advantageous features such as increased bioavailability, stability, or reduced host immune recognition. One or more amino acid insertions may be introduced into a peptide of the formula I preferably outside the sequence A 2 -X 2 -Asn-X 3 -X 4 -P.Tyr-X 5 . For example, amino acid insertions may be made between X 1 and A 1 or between X 5 and X 6 , or X 6 and X 7 . Amino acid insertions may consist of a single amino acid residue or sequential amino acids. One or more amino acids, preferably one to five amino acids, may be added to the right or left termini of a peptide of the invention. Examples of such analogs include Ala- Leu-Leu-Leu-Ser-Asn-Pro-Ala-P.Tyr.-Arg-Leu-Leu-Leu-Ala; Gly-Pro-Leu-Tyr-Ala-Ser- Ser-Asn-Pro-Glu-P.Tyr-Leu-Ser-Ala-Ser-Asp-Val-Phe; Pro-Val-Ser-Val-Asρ-Asn-Pro-Glu- P.Tyr-Leu-Leu-Asn-Ala-Gln-Lys; Leu-Ser-Leu-Leu-Ser-Asn-Pro-Thr-P.Tyr-Ser-Val-Met- Arg-Ser-Lys; Val-Ser-Ser-Leu-Asn-Glu-Met-Ile-Asn-Pro-Asn-P.Tyr-Ile-Gly-Met-Gly-Pro- Phe; and Leu-Leu-Leu-Thr-Lys-Pro-Glu-Met-Phe-Glu-Asn-Pro-Leu-P.Tyr-Gly-Ser-Val- Ser-Ser-Phe (SEQ. ID. NOs. 20 to 25 in the Sequence Listing). Deletions may consist of the removal of one or more amino acids, or discrete portions from the peptide sequence preferably outside the A 2 -X 2 -Asn-X 3 -X 4 -P.Tyr sequence. The deleted amino acids may or may not be contiguous. The lower limit length of the resulting analog with a deletion mutation is about 7 amino acids. It is anticipated that if amino acids are inserted or deleted in sequences outside the A 2 -X 2 -Asn-X 3 -X 4 -P.Tyr sequence that the resulting analog of the peptide will exhibit the activity of a peptide of the invention. Cyclic derivatives of the peptides of the invention are also part of the present invention. Cyclization may allow the peptide to assume a more favorable conformation for association with a PTB domain containing protein. Cyclization may be achieved using techniques known in the art. For example, disulfide bonds may be formed between two appropriately spaced components having free sulfhydryl groups, or an amide bond may be formed between an amino group of one component and a carboxyl group of another component. Cyclization may also be achieved using an azobenzene-containing amino acid as described by Ulysse, L., et al., J. Am. Chem. Soc. 1995, 117, 8466-8467. The side chains of P.Tyr and Asn may be linked to form cyclic peptides. The components that form the bonds may be side chains of amino acids, non-amino acid components or a combination of the two. Preferred cyclic peptides of the invention include cyclo-(Ile-Glu-Asn-Pro-Gln- P.Tyr-Phe-Ser-Pro-Gly, and cyclo-(He-Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser-Asp-Ala-Pro- Gly) (SEQ. ID. NOs. 26 to 27 in the Sequence Listing) where the amino group of isoleucine and the carboxyl group of glycine form a peptide bond; cyclo-(His-Ile-Ile-Glu-Asn-Pro- Gln-P.Tyr-Phe-Ser-Asp-Ala-Pro-Gly) (SEQ. ID. NO. 28 in the Sequence Listing) where the amino group of histidine and the carboxyl group of glycine form a peptide bond; and Cys-Ile-Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Cys (SEQ. ID. NO. 29 in the Sequence Listing) having a disulphide bond between the two cysteine residues. In an embodiment of the invention, cyclic peptides are contemplated that have a beta-turn in the right position. Beta-turns may be introduced into the peptides of the invention by adding the amino acids Pro-Gly at the right position. An example of such a cyclic peptide is a peptide of the invention with an He in the left position (i.e. a terminal A 1 or A 2 is He) and the amino acids Pro-Gly at the right position. The amino group of the He and the carboxyl group of the Gly form a peptide bond resulting in a cyclic peptide. The 3D structure of the cyclic peptide is similar to the original structure of the PTB binding site of TrkA. The following is an example of a cyclic peptide that has a beta-turn in the right position: cyclo-(Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser-Pro-Gly) (SEQ. ID. NO. 26 in the Sequence Listing). In this peptide, Asn-Pro-Gln-P.Tyr take a native beta-turn, Ser-Pro-Gly- Ile make another beta-turn on the other side, and the central part adopts an antiparallel beta- sheet. A beta-sheet has two faces, and the peptide binds to the PTB domain with the face on which the side chains of He, Asn, and P.Tyr extend. The side chains of Glu and Phe are on the other face, and may not affect the binding affinity. It may be possible to control the binding specificity by the side-chain of Gin as this side chain may contact the PTB domain. It may be desirable to produce a cyclic peptide which is more flexible than the cyclic peptides containing peptide bond linkages as described above. A more flexible peptide may be prepared by introducing cysteines at the right and left position of the peptide and forming a disulphide bridge between the two cysteines. The two cysteines are arranged so as not to deform the beta-sheet and turn. The peptide is more flexible as a result of the length of the disulfide linkage and the smaller number of hydrogen bonds in the beta-sheet portion. The relative flexibility of a cyclic peptide can be determined by molecular dynamics simulations The invention also includes a peptide conjugated with a selected peptide, protein, or a selectable marker (see below) to produce fusion proteins. For example, a peptide of the invention may be conjugated with a peptide which facilitates entry into cells. The peptides of the invention may be converted into pharmaceutical salts by reacting with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, etc., or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, benezenesulfonic acid, and toluenesulfonic acids. The peptides of the invention may be prepared using recombinant DNA methods. Accordingly, nucleic acid molecules which encode a peptide of the invention may be incoφorated in a known manner into an appropriate expression vector which ensures good expression of the peptide. Possible expression vectors include but are not limited to cosmids, plasmids, or modified viruses so long as the vector is compatible with the host cell used. The expression vectors contain a nucleic acid molecule encoding a peptide of the invention and the necessary regulatory sequences for the transcription and translation of the inserted protein-sequence. Suitable regulatory sequences may be obtained from a variety of sources, including bacterial, fungal, viral, mammalian, or insect genes (For example, see the regulatory sequences described in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Selection of appropriate regulatory sequences is dependent on the host cell chosen, and may be readily accomplished by one of ordinary skill in the art. Other sequences, such as an origin of replication, additional DNA restriction sites, enhancers, and sequences conferring inducibility of transcription may also be incoφorated into the expression vector. The recombinant expression vectors may also contain a selectable marker gene which facilitates the selection of transformed or transfected host cells. Suitable selectable marker genes are genes encoding proteins such as G418 and hygromycin which confer resistance to certain drugs, β-galactosidase, chloramphenicol acetyltransferase, firefly luciferase, or an immunoglobulin or portion thereof such as the Fc portion of an immunoglobulin preferably IgG. The selectable markers may be introduced on a separate vector from the nucleic acid of interest. The recombinant expression vectors may also contain genes which encode a fusion portion which provides increased expression of the recombinant peptide; increased solubility of the recombinant peptide; and/or aid in the purification of the recombinant peptide by acting as a ligand in affinity purification. For example, a proteolytic cleavage site may be inserted in the recombinant peptide to allow separation of the recombinant peptide from the fusion portion after purification of the fusion protein. Examples of fusion expression vectors include pGEX (Amrad Coφ., Melbourne, Australia), pMAL (New England Biolabs, Beverly, MA) and pRIT5 (Pharmacia, Piscataway, NJ) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the recombinant protein. Recombinant expression vectors may be introduced into host cells to produce a transformant host cell. Transformant host cells include prokaryotic and eukaryotic cells which have been transformed or transfected with a recombinant expression vector of the invention. The terms "transformed with", "transfected with", "transformation" and "transfection" are intended to include the introduction of nucleic acid (e.g. a vector) into a cell by one of many techniques known in the art. For example, prokaryotic cells can be transformed with nucleic acid by electroporation or calcium-chloride mediated transformation. Nucleic acid can be introduced into mammalian cells using conventional techniques such as calcium phosphate or calcium chloride co-precipitation, DEAE-dextran- mediated transfection, lipofectin, electroporation or microinjection. Suitable methods for transforming and transfecting host cells may be found in Sambrook et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory press (1989)), and other laboratory textbooks. Suitable host cells include a wide variety of prokaryotic and eukaryotic host cells. For example, the peptides of the invention may be expressed in bacterial cells such as E. coli, insect cells (using baculovirus), yeast cells or mammalian cells. Other suitable host cells can be found in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1991). The peptides of the invention may be tyrosine phosphorylated using the method described in Reedijk et al. (The EMBO Journal 11(4): 1365, 1992). For example, tyrosine phosphorylation may be induced by infecting bacteria harbouring a plasmid containing a nucleotide sequence encoding a peptide of the invention, with a λgtl 1 bacteriophage encoding the cytoplasmic domain of the Elk tyrosine kinase as a LacZ-Elk fusion. Bacteria containing the plasmid and bacteriophage as a lysogen are isolated. Following induction of the lysogen, the expressed peptide becomes phosphorylated by the Elk tyrosine kinase. The peptides of the invention may also be prepared by chemical synthesis using techniques well known in the chemistry of proteins such as solid phase synthesis (Merrifield, 1964, J. Am. Chem. Assoc. 85:2149-2154) or synthesis in homogenous solution (Houbenweyl, 1987, Methods of Organic Chemistry, ed. E. Wansch, Vol. 15 1 and II, Thieme, Stuttgart). By way of example, the peptides may be synthesized using 9- fluorenyl methoxycarbonyl (Fmoc) solid phase chemistry with direct incoφoration of phosphotyrosine as the N-fluorenylmethoxy-carbonyl-O-dimethyl phosphono-L-tyrosine derivative. N-terminal or C-terminal fusion proteins comprising a peptide of the invention conjugated with other molecules may be prepared by fusing, through recombinant techniques, the N-terminal or C-terminal of the peptide, and the sequence of a selected protein or selectable marker with a desired biological function. The resultant fusion proteins contain the peptide fused to the selected protein or marker protein as described herein. Examples of proteins which may be used to prepare fusion proteins include immunoglobulins, glutathione-S-transferase (GST), hemagglutinin (HA), and truncated myc. The peptides of the invention may be used to prepare monoclonal or polyclonal antibodies. Conventional methods can be used to prepare the antibodies. As to the details relating to the preparation of monoclonal antibodies reference can be made to Goding, J.W., Monoclonal Antibodies: Principles and Practice, 2nd Ed., Academic Press, London, 1986. As discussed below, the antibodies may be used to identify proteins with PTB domain binding sites. The peptides and antibodies specific for the peptides of the invention may be labelled using conventional methods with various enzymes, fluorescent materials, luminescent materials and radioactive materials. Suitable enzymes, fluorescent materials, luminescent materials, and radioactive material are well known to the skilled artisan. Labeled antibodies specific for the peptides of the invention may be used to screen for proteins with PTB domain binding sites, and labeled peptides of the invention may be used to screen for PTB domain containing proteins such as She. The peptides of the invention interfere with the interaction of a PTB domain containing protein and a PTB domain binding site. The term "PTB domain containing protein" refers to a protein or peptide which comprises or consists of a PTB domain. A PTB domain is a region which is a domain of -160 amino acids which was originally identified in She and Sck (Kavanaugh, V.M. Et al., 1995 Science, 268.1177-1179; Bork, RP, and Margolis, B, Cell, Vol 80:693-694, 1995; Craparo, A., et al., 1995, J. Biol. Chem. 270:15639-15643; van der Geer, P., & Pawson, T., 1995, TBS 20:277-280; Batzer, A.G., et al., Mol. Cell. Biol. 1995, 15:4403-4409; and Trub, T., et al., 1995, J. Biol. Chem. 270:18205-18208; van der Geer et al., Current Biology 5(4):404, 1995)). The PTB domain comprises residues 46 to 208 in the 52 kDa isoform of She. The sequences of several known PTB domains are aligned in Figure 7. In Figure 7, residues that are conserved within the sequences are shaded. Examples of PTB domain containing proteins are mammalian She and Sck, IRS-1, and homologues of She including Drosophila She, and mouse She. Other proteins that contain homologous PTB domains have been identified using data base search methods (Bork, RP, and Margolis, B. Cell, Vol 80:693-694, 1995). PTB domain containing proteins may also be identified by screening a cDNA expression library with a protein containing a sequence with high affinity to PTB domains, i.e. a PTB domain binding sequence or a peptide of the invention which may be labeled. PTB domain containing proteins may also be screened using antibodies specific for the PTB domain. For example, a PTB domain that binds to the consensus sequence Leu/Ile-X- Asn-Pro-X-P.Tyr found in growth factors may be identified by screening a cDNA expression library with proteins based on the consensus sequence. PCR (Wilks, A.F., Proc. Natl. Acad. Sci. U.S.A. Vol. 86, pp. 1603-1607, March 1989) or low stringency screening (Hanks, S.K., Proc. Natl. Acad. Sci. U.S.A. Vol. 84, pp 388-392, January 1987) with the PTB domain specific probe can be used. The term " PTB domain binding site" refers to a sequence with high affinity to PTB domains. PTB domain binding sequences have been identified in activated growth factors such as activated nerve growth factor receptor, activated epidermal growth factor (EGF) receptor, polyoma middle T antigen, and SHIP (Blaikie et al, 1994; Kavanaugh and Williams, 1994; van der Geer et al, 1995; Damen et al, 1996), ErbB2, ErbB3, TrkA, TrkB, TrkC, MCKlOb, insulin receptor, IGF-1 receptor, and JL-4 receptor. PTB domain binding sites may be identified by screening with PTB domain containing proteins or with antibodies specific for the peptides of the invention. The phrase "interfere with the interaction of refers to the ability of the peptides of the invention to inhibit the binding of a PTB domain containing protein to a PTB domain binding site thereby affecting regulatory pathways that control gene expression, cell division, cytoskeletal architecture and cell metabolism. Examples of such regulatory pathways are the Ras pathway, the pathway that regulates the breakdown of polyphosphoinositides through phospholipase C, and PI-3-kinase activated pathways, such as the rapamycin-sensitive protein kinase B (PKB/Akt) pathway. The peptides of the invention have been specifically shown to interfere with the interaction of the PTB domain of She and phosphotyrosine-containing peptides based on the sequence around Tyr 490 in activated nerve growth factor receptor and based on the She binding site in polyoma middle T antigen. Accordingly, the activity of a peptide of the invention may be confirmed by assaying for the ability of the peptide to interfere with the interaction of the PTB domain of She and phosphotyrosine-containing peptides based on the sequence around Tyr 490 in activated nerve growth factor receptor, or based on the She binding site in polyoma middle T antigen. Computer modelling techniques known in the art may also be used to observe the interaction of a peptide of the invention, and truncations and analogs thereof with a PTB domain containing protein (for example, Homology Insight II and Discovery available from BioSym/Molecular Simulations, San Diego, California, U.S.A.). If computer modelling indicates a strong interaction, the peptide can be synthesized and tested for its ability to interfere with the binding of the PTB domain of She and phosphotyrosine-containing peptides as discussed above. The peptides of the invention mediate the interactions of PTB domain containing proteins with PTB domain binding sites on proteins such as growth factors and cytokine receptors which regulate pathways that control gene expression, cell division, cytoskeletal architecture and cell metabolism. The peptides may therefore be used in the treatment of conditions involving perturbation of such regulatory pathways. In particular, the peptides may be useful in treating disorders involving excessive proliferation including various forms of cancer such as leukemias, lymphomas (Hodgkins and non-Hodgkins), sarcomas, melanomas, adenomas, carcinomas of solid tissue, hypoxic tumors, squamous cell carcinomas of the mouth, throat, larynx, and lung, genitourinary cancers such as cervical and bladder cancer, hematopoietic cancers, head and neck cancers, and nervous system cancers, ovarian cancer, breast cancer, glioblastoma, benign lesions such as papillomas, arthrosclerosis, angiogenesis, and viral infections, in particular HIV infections; and autoimmune diseases including systemic lupus erythematosus, Wegener's granulomatosis, rheumatoid arthritis, sarcoidosis, polyarthritis, pemphigus, pemphigoid, erythema multiforme, Sjogren's syndrome, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, keratitis, scleritis, Type I diabetes, insulin-dependent diabetes mellitus, Lupus Nephritis, and allergic encephalomyelitis. The invention also relates to a pharmaceutical composition comprising a peptide of the invention for use as an antagonist of the interaction of a PTB domain containing protein, preferably She and a PTB domain binding site, preferably an activated growth factor or cytokine receptor. The peptides of the invention may be formulated into pharmaceutical compositions for adminstration to subjects in a therapeutically active amount and in a biologically compatible form suitable for administration in vivo i.e. a form of the peptides to be administered in which any toxic effects are outweighed by the therapeutic effects. The peptides may be administered to living organisms including humans, and animals. A therapeutically active amount of the pharmaceutical compositions of the invention is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result. For example, a therapeutically active amount of a peptide may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regime may be adjusted to provide the optimum therapeutic response. The peptides may be administered in a convenient manner such as by injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration. Depending on the route of administration, the peptides may be coated in a material to protect them from the action of enzymes. The peptides may also be used in combination with organic substances for prolongation of their pharmacologic actions. Examples of such organic substances are non-antigenic gelatin, carboxymethylcellulose, sulfonate or phosphate ester of alginic acid, dextran, polyethylene glycol and other glycols, phytic acid, polyglutamic acid, and protamine. The compositions described herein can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of a peptide is combined in a mixture with a pharmaceutically acceptable vehicle. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985). On this basis, the compositions include, albeit not exclusively, solutions of the peptides in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids. The peptides may also be incoφorated in liposomes or similar delivery vehicles. The utility of the peptides and compositions of the invention may be confirmed in in vitro cell penetration assays. For example, the effects of the peptides upon cellular functions in vivo may be confirmed using electroporation techniques (See Raptis, L., and K.L. Firth, DNA and Cell Biology, 9:615, 1990 and Raptis, L.H. Et al., BioTechniques 18: 104, 1995). The utility of the peptides and compositions of the invention may also be confirmed in in vivo animal experimental model systems. For example, therapeutic utility in proliferative disorders may be tested by examining the ability of a substance to suppress the growth of a transplantable tumor. Particular in vivo animal models which may be used include the growth of human tumor cell lines (e.g. glioblastomas) in nude mice; and the development of tumors in mice that carry MMTV-polyomavirus middle T antigen or MMTV-neu transgenes, which result in the development of mammary carcinoma. The following non-limiting examples are illustrative of the present invention: EXAMPLES Example 1 The following materials and methods were utilized in the investigations outlined in the example: MATERIALS AND METHODS Cell lines, anti-sera and fusion proteins. CHO cells expressing Wt insulin receptors (White etal, 1988) were grown in F12 medium containing 25 mM Hepes pH 7.4, and 10% fetal bovine serum. NLH3T3 cells expressing Wt and Phe 490 mutant NGF receptor (Stephens et al, 1994) were grown Dulbecco-Vogt's modified Eagle medium (DMEM) containing 10% calf serum (CS). NIH3T3 cells overexpressing the human EGF receptor (Honegger et al, 1987) were grown in DMEM containing 10% CS and 400 μg/ml G418. The monoclonal anti-insulin receptor antibody 51 was obtained from Dr. I. Goldfine (Forsayeth etal, 1987; Roth et al, 1982). A polyclonal anti-NGF receptor antiserum was raised against NGF receptor carboxy-terminus (Hempstead et al, 1992), the anti-She polyclonal serum was raised against a GST-Shc SH2 domain fusion protein. The anti-P.Tyr monoclonal Antibody 4G10 was obtained from UBI (Lake Placid NY). The GST-Shc PTB fusion protein used in the receptor binding experiments described here is identical to GST- ShcB described in van der Geer et al, 1995. The GST-dShc PTB fusion protein has been described previously (Lai et al, 1995). Immunoprecipitations and PTB binding assays. Cells were grown to confluence and starved 16 hr in medium without serum. CHO cells expressing the insulin receptor were stimulated with 100 nM insulin for 5 min at 37°C. NLH3T3 cells expressing NGF receptors were stimulated with 50 ng/ml NGF for 5 min at 37°C, and NLH3T3 cells expressing the human EGF receptor were stimulated with 100 ng/ml EGF for 5 min at 37°C. Control and growth factor stimulated cells were rinsed twice with cold PBS and lysed in 1 ml 50 mM Hepes pH 7.5, 150 mM NaCl, 10% glycerol, 1% Triton X100, 1.5 mM MgCl 2 , 1 mM EGTA, 100 mM NaF, 10 mM Sodium Pyrophosphate, 500 μM Sodium Vanadate, 1 mM PMSF, 10 μg/ml Aprotinin, and 10 μg/ml Leupeptin (PLC-lysis buffer) per 10 cm dish. Immunoprecipitations and PTB-binding assays in the absence or presence of 2 or 5 μM competing phosphopeptide were performed exactly as described previously (van der Geer et al, 1995). Surface Plasmon Resonance analysis of phosphopeptides interacting with the She PTB domain. Peptides were synthesized using 9-fluorenyl methoxycarbonyl (Fmoc) solid phase chemistry with direct incoφoration of phosphotyrosine as the N"-fluorenylmethoxy- carbonyl-O-dimethyl-phosphono-L-tyrosine derivative. Cleavage of the peptide from the resin and deprotection was achieved through an 8 hr incubation at 4°C in trifluoroacetic acid containing 2 M bromotrimethyl silane and a scavenger mixture composed of thioanisole, m-cresol and 1,2-ethanedithiol (1.0 : 0.5 : 0.1% by volume). The product was precipitated with cold t-butyl ethylether and collected by centrifugation. Following desalting of the crude material, pure phosphopeptide was isolated using reverse phase HPLC. The authenticity of the phosphopeptide was confirmed by amino acid analysis and mass spectroscopy. Surface plasmon resonance analysis was carried out using a Biacore apparatus (Pharmacia Biosensor) as described previously (Puil et al, 1994). The peptide L-S-L-L-S- N-P-T-p. Y-S-V-M-R-S-K was immobilized to a biosensor chip through injection of a 0.5 mM solution of the phosphopeptide, in 50 mM HEPES, pH 7.5 and 2 M NaCl, across the chip surface previously activated following procedures outlined by the manufacturer. Injection of anti-phosphotyrosine antibody was used to confirm that successful immobilization of the peptide was achieved. Solutions (100 μl) containing 1 μM GST-Shc PTB domain fusion protein and the indicated concentrations of soluble phosphopeptide in 50 mM Na phosphate, pH 7.5, 150 mM NaCl, 0.1 mM EDTA, and 2 mM DTT, were injected across the surface. The amount of bound GST-Shc PTB domain was estimated from the surface plasmon resonance signal at a fixed time following the end of the injection and the percentage bound, relative to injection of GST-Shc PTB domain alone, calculated. The surface was regenerated using 2 M Guanidinium-HCl. Expression of Torso-DER in transgenic flies. Transgenic flies expressing the activated Torso-DER chimeric protein expressed under the control of the heat shock promoter were obtained and protein expression was induced by growing the flies at 37°C for 45 min after which they were allowed to recover at room temperature for 2.5 hr. Lysates were made as described before (Lai et al, 1995). I. Identifying Motifs Recognized by the She PTB Domain The PTB domain was found to bind tyrosine phosphorylated proteins that contain phosphorylation sites present within the sequence Asn-Pro-X-P.Tyr. To confirm that it is indeed the Asn-Pro-X-P.Tyr motif that is recognized by the PTB domain, it was shown that peptides that contain a phosphotyrosine within the sequence Asn-Pro-X-P.Tyr can compete for binding of the She PTB domain to activated growth factor receptors. The specificity was confirmed by sequencing peptides present in a degenerate phosphopeptide library that bind to the She PTB domain (Songyang etal, 1995). To investigate the contribution of the Asn and Pro residues within the consensus PTB domain binding site to phosphopeptide recognition, the residues were changed to Ala in a phosphopeptide based on the sequence around Tyr 490, the She-binding site in the NGF receptor. Wt and mutant peptides were tested for their ability to compete with NGF receptors, present in lysates of NGF-stimulated cells, for binding to a GST fusion protein containing the She PTB domain (Figure IA). Bound proteins were detected by anti-P.Tyr immunoblotting. Only the activated NGF receptor bound the She PTB domain in vitro. The Wt phosphopeptide (His-Ile-Ile-Glu-Asn- Pro-Gln-P. Tyr-Phe-Ser-Asp) competed efficiently for binding. Changing the Asn at position -3 (relative to the P.Tyr) to Ala completely abolished binding, whereas changing the Pro at -2 to Ala reduced the affinity of the PTB-peptide interaction. The identity of the NGF receptor was confirmed by stripping and reprobing the blot with a polyclonal antiserum raised against the NGF receptor (Figure IB). To confirm these results and to estimate the contribution of the different residues more precisely, a wide range of concentrations of the different peptides was tested for their ability to inhibit binding of the She PTB domain to a phosphotyrosine-containing peptide, based on the sequence around Tyr 250 the She-binding site in polyoma middle T antigen, immobilized on a Biacore chip (Figure 2). The data show that within the Asn-Pro-X-P.Tyr motif the Asn residue is essential for peptide binding by the PTB domain; presence of the Pro residue further increases the affinity approximately ten fold (Table 1). PTB binding depends on phosphorylation of the Tyr residue present within the consensus binding site (Blaikie et al, 1994; Kavanaugh and Williams, 1994; van der Geer et al, 1995). These results are consistent with the presence of Asn-Pro-X-P.Tyr motifs in a variety of receptors for growth factors and cytokines that have been shown to bind She. H. Why the Insulin Receptor Lacks the Ability to bind to She The insulin receptor, which contains a bona fide autophosphorylation site that is present within the sequence Asn-Pro-Glu-P.Tyr, lacks the ability to bind to She (Kovacina and Roth, 1993; Pronk et al, 1993). Tyr 960 in the insulin receptor is present in the juxta membrane domain, between the membrane and the kinase domain, in a position very similar to Tyr 490 in the NGF receptor (see Figure 3). The inability of the insulin receptor to associate stably with She was confirmed in coimmunoprecipitation experiments in which She immunoprecipitates were analyzed for associated proteins by anti-P.Tyr immunob lotting (Figure 4A). Wt but not Phe 490 mutant NGF receptors can be detected in She immunoprecipitates from NGF-stimulated cells. In contrast, insulin receptors were absent from She immunoprecipitates from insulin stimulated CHO cells overexpressing the Wt insulin receptor (CHO-IR cells). To test whether the insulin receptors inability to associate with She in cells was reflected in an inability to bind to the She PTB domain in vitro, GST fusion proteins containing the She PTB domain were incubated with lysates of control and insulin-stimulated CHO-IR cells and bound proteins were visualized by anti- P.Tyr immunoblotting. Wt and Phe 490 NGF receptors were included as controls. The NGF receptor bound to the She PTB domain in vitro (Figure 4B) and binding was dependent on phosphorylation of the NGF receptor at Tyr 490. In contrast, no tyrosine phosphorylated insulin receptors were bound to the She PTB domain in vitro (Figure 4B). To investigate the possibility that access to the Asn-Pro-X-P.Tyr motif in the insulin receptor is blocked, the ability of the phosphotyrosine-containing peptide based on the sequence around Tyr 960 in the insulin receptor to compete with the NGF receptor for binding to the She PTB domain was tested. In contrast to the NGF receptor phosphopeptide, the insulin receptor peptide was unable to compete (Figure 5 A, lanes 2 and 6, and Figure 5B). This indicates that the inability of the insulin receptor to bind the PTB domain is retained in this phosphopeptide that starts seven amino acid residues amino- terminal to the P.Tyr (Table 1). The NGF receptor and several other proteins with well defined She-binding sites often contain large aliphatic residues at six and five residues amino-terminal of the phosphorylated Tyr residue. These large aliphatic residues are absent from the insulin receptor, which has an Ala and a Ser six and five residues amino-terminal to Tyr 960 (Table 1). To test the possibility that these residues are important for PTB binding, several substitutions at these positions were made in the NGF receptor peptide and mutant peptides were tested for their ability to block binding of the PTB domain to the NGF receptor and to the polyoma middle T antigen phosphopeptide. Changing the He six residues upstream of the P.Tyr to an Ala had no effect on the ability to bind to the PTB domain (Figure 5A and 5B). In contrast, changing the He at -5 to Ala in addition to changing the He at -6 reduced the ability to bind to the PTB domain (Figure 5 A and 5B). Changing the He residues at -5 to a Ser in addition to changing the He at -6 to Ala, identical to what is found in the insulin receptor, abolished binding (Figure 5 A and 5B). These data clearly implicate the aliphatic residues five and six residues amino-terminal to the phosphotyrosine in the PTB-binding site as being important for binding to the She PTB domain and suggest that changing the Ser, five residues upstream of the P.Tyr in the insulin receptor peptide, to an He should increase its ability to bind to the PTB domain dramatically This was tested and it was found that in contrast to the Wt insulin receptor peptide, which has no measurable affinity for the PTB domain, the mutant insulin receptor peptide competed efficiently with the NGF receptor and the NGF receptor peptide for binding to the PTB domain (Figs. 5A and 5B) The data presented here (summarized in Table 1) indicate that the She PTB domain specifically recognizes P Tyr residues in the context of a Asn at -3 and a large aliphatic at -5 or -6 A Pro residue at -2 increases the affinity but appears to be non-essential DX Characterization of the PTB Domain of She A comparison of the PTB domains present in She and its relatives revealed the presence of a large number of conserved Arg residues Several conserved Arg are directly involved in P.Tyr binding by SH2 domains As an initial attempt to characterize PTB domain P.Tyr-binding, all conserved Arg residues in the She PTB domain were individually mutated and GST-fusion proteins containing mutant PTB domains were tested for their ability to bind to the activated NGF receptor (Fig 6A) The three Arg residues and the Lys that are present between residues 97 and 100 were mutated to Met in combination Of all ten Arg residues tested, only mutation of Arg 175 had a dramatic effect on the affinity of the She PTB domain for the activated NGF receptor (Figure 6A) Both the Met 175 and the Lys 175 mutants were strongly impaired in their binding activity (Figures 6 A and 6B), indicating that not just a positive charge but a positive charge in the context of an Arg residue is required at this position The dShc PTB domain contains an Arg at residue 151, which is homologous to Arg 175 in the human She Wt and mutant dShc PTB domains were tested for their ability to bind to the drosophila EGF receptor (DER) (Figure 6B) The ability of Wt and the 175 mutant human She PTB domains to bind to the human EGF receptor were tested in parallel (Figure 6B) The Wt dShc PTB domain but not the Arg to Ala mutant at position 151 was able to bind efficiently to activated DER in vitro, suggesting that the requirement for the presence of an Arg residue at position 175 in the human She PTB domain has been conserved in evolution Summary She binding to activated growth factor receptors appears to be an important step in the initiation of signal transduction towards DNA synthesis and cell division or differentiation She binding sites are particularly well characterized in the NGF receptor and in polyoma middle T antigen In the NGF receptor She binds to Tyr 490 in the juxta membrane domain (Figure 3) Mutation of Tyr 490, in addition to mutation of the PLCγ- binding site, completely blocks NGF-induced neuronal differentiation in PC 12 cells (Stephens et al, 1994). Mutation of Tyr 250, which is the She binding site, in polyoma middle T antigen blocks cellular transformation (Campbell et al, 1994; Dilworth et al, 1994). The EGF receptor also interacts strongly with She, although the precise contribution of different autophosphorylation sites in the EGF receptor carboxy-terminus remains unresolved (Batzer et al, 1994; Okabayashi et al, 1994). The PTB domain at the amino-terminus of She may be the important mediator of She-growth factor receptor interactions. Asn-Pro-X-P.Tyr motifs are conserved in a large number of She binding proteins and Asn-Pro-X-P.Tyr-containing peptides compete efficiently for She PTB binding to activated growth factor receptors, such as the receptors for EGF and NGF (Blaikie etα/., 1994; Campbell et al, 1994; Kavanaugh et al, 1995; van der Geer and Pawson, 1995; van der Geer et al, 1995). Using peptide binding studies with mutant peptides, the present inventors characterized the nature of the PTB-binding site. The presence of an Asn residue three residues amino-terminal to the P.Tyr appears to be absolutely essential for binding to the PTB domain. In contrast, the Pro appears to be dispensable for binding to the PTB domain in vitro. Addition of the Pro increases the affinity and this may be important for binding in vivo, consistent with the observation that the Pro appears to be conserved in many She PTB-binding sites. It was found that the activated insulin receptor, which also has an autophosphorylation site contained within an Asn-Pro-X-Tyr motif, does not bind stably to She in vivo or in vitro (Kovacina and Roth, 1993; Pronk et al, 1993). She, however, becomes phosphorylated in response to insulin and the She PTB domain was shown to interact with Tyr 960 in the insulin receptor using the two-hybrid method in yeast (Gustafson et al, 1995). The present inventors have shown that the presence of an aliphatic residue five or six residue amino-terminal to the P.Tyr is important for high affinity binding by the She PTB domain. A phosphopeptide with two Ala residues at these positions still binds to the She PTB domain but with an affinity that is approximately three fold lower than that for binding of a phosphopeptide with an He at either position -6 or -5 (Table 1). The presence of a Ser five residues amino-terminal to the P.Tyr disrupts high affinity binding completely. A peptide, derived from the insulin receptor, that lacked the ability to bind to the She PTB domain was changed into a PTB-binding site with a single amino acid substitution at a residue outside the Asn-Pro-X-P.Tyr motif. Conversely, the ability to bind the She PTB domain was destroyed by a single amino acid change outside the Asn-Pro-X- P.Tyr motif in an NGF receptor derived phosphopeptide (Table 1). It appears that different PTB domains all recognize Asn-Pro-X-P.Tyr or Asn-X-X-P.Tyr and that further specificity results from interactions of the PTB domain with amino acid residues outside this recognition motif. Furthermore, the presence of particular residues at certain positions within the binding site could prohibit certain PTB domains from binding without affecting the binding of other PTB domains. This is partially illustrated by the observation that the presence of a Ser five residues amino-terminal to the P.Tyr prevents binding of the She PTB domain. An understanding of PTB-binding specificity enables accurate predictions to be made as to which proteins will bind to particular PTB-containing adaptor or signalling molecules. In addition, it enables manipulation of the repertoire of PTB domain-containing proteins that are recruited by growth factor receptors without changing the actual phosphate acceptor sites. For instance, phosphorylation of both the insulin receptor substrate 1 (LRS-1) and She appears to depend on a low affinity interaction with the insulin receptor at Tyr 960 (Backer et al, 1990; White et al, 1988; Yonezawa et al, 1994). By changing residues amino-terminal of the Asn-Pro-X-P.Tyr motif it may be possible to abolish specifically phosphorylation of either one of these polypeptides by the insulin receptor. Conversely, it may be possible to create an insulin receptor that interacts much stronger with either She or IRS- 1. Several Arg residues that are conserved in SH2 domains have been shown to be directly involved in P.Tyr binding (Pawson, 1995; Pawson and Gish, 1992). Based on its functional homology with the SH2 domain further characterization of the PTB domain by mutagenesis of Arg residues that are conserved in the PTB domains of different members of the She family has been carried out. The FLVRES sequence (Phe-Leu-Val-Arg-Glu-Ser) has been conserved between SH2 domains with the Arg being the only invariant residue present in all SH2 domains described thus far (Pawson, 1995; Pawson and Gish, 1992). An Arg residue present within the sequence YLVRYM (Tyr-Leu-Val-Arg-Tyr-Met) (residues 52-57), possibly representing a rudimentary FLVRES motif in the She PTB domain, was mutated without an effect on its ligand-binding abilities; mutation of this residue in SH2 domains destroys their ability to bind to phosphotyrosine (Marengere and Pawson, 1992; Mayer et al, 1992). This is consistent with the notion that PTB and SH2 domains are structurally unrelated. The studies described herein have defined an Arg residue in the carboxy-terminus of the PTB domain that is important for its interaction with activated growth factor receptors. This Arg residue is conserved in dShc and its presence was found to be essential for binding of the dShc PTB domain to DER, the drosophila homolog of the EGF receptor. Thus the need for this Arg residue for PTB-ligand interaction has been conserved in evolution between drosophila and man. As indicated earlier, She appears to be important for signal transduction downstream of growth factor and cytokine receptors (Burns et al, 1993; Crowe et al, 1994; Cutler et al, 1993; Lanfrancone et al, 1995; Pelicci et al, 1992; Pronk et al, 1993; Ravichandran etal, 1993; Segatto et al, 1993; Yokote et al, 1994). There is evidence that She may be involved in Ras activation presumably through its interaction with Grb2 and Sos (Buday and Downward, 1993; Crowe et al, 1994; Egan et al, 1993; Gale et al, 1993; Li et al, 1993; Myers et al, 1994; Rozakis-Adcock et al, 1993; Rozakis-Adcock et al, 1992; Salcini et al, 1994; Sasaoka t /., 1994). Example 2 The ability of the peptides listed in Table 2 to inhibit the binding of human She PTB domains to activated EGF -receptor (R) or NGF-R (Trk) was investigated. The following materials and methods were used in the assays: Peptides. The peptides are listed in Table 2. In Table 2 the designation "C" refers to a cyclic peptide; C-1,3,4,5 are cyclized by the amino- and carboxyl termini by an amide bond; C-2 is cyclized by a disulfide bond between two cysteines on each of the N- and C-termini;"P" refers to peptides which have penetrating sequences on the N-terminus where P-l and P-2 are basic charged penetrating sequences with the latter having phosphorylated tyrosine residues; P-3 and P-4 have a hydrophobic penetrating sequence with the latter having phosphorylated tyrosine residues; and "P-5" was obtained by coupling with penetratin 1 (Appligene) and CGHIIENPQPYFSD. Fusion Proteins. GST-ShcB and GST-R175M fusion proteins were prepared as described in van der Geer et al., 1995. In vitro binding assay. HER14 cells (3T3 cells expressing EGF-R) were starved in 0.5% CS media for 24 hours and stimulated with 100 ng/ml EGF for 5 min. Cells were lysed and mixed with GST, GST-ShcB or GST-R175M beads. Proteins which bound to beads were resolved on SDS-PAGE and detected by anti-phospho-Tyr antibody (4G10) or by anti-EGF- R . Results: Inhibition of Binding by Peptides In Vitro. The peptides listed in Table 2 were added to cell lysates at 5 μM, incubated for 30 min., and treated with GST-ShcB beads. Proteins bound to GST-ShcB were detected by anti-phospho-Tyr antibody. A peptide having the She PTB binding motif of Trk inhibited the association of She and EGF-R while a peptide with an amino acid substitution from Asn to Ala (Trk N to A), or an IRS-1 binding site of insulin receptor (Ins) did not inhibit (Figure 8, Panel A). The peptide designated C-2 inhibited the binding of She and EGF-R completely in vitro (Figure 8, Panels A, B). P-2, dissolved in Hepes buffer and precipitated, showed weak inhibition (Figure 8, Panel B). The experiment was repeated with the peptides dissolved in DMSO (Figure 9). P-2 dissolved in DMSO solution showed strong inhibition at 5 μM; C-2 inhibited complex formation as described previously; and P-l, which is not phosphorylated on Tyr residues did not inhibit the association of She and EGF-R at 100 μM. The dose responses of the peptides was investigated using the in vitro binding assay. While C-2 showed strong inhibition at 5 μM, C-3, C-4, and C-5, did not inhibit (Figure 10, Panel A). C-l exhibited, about 50% inhibition at lOOμM (Figure 10, Panel A). P-2 (dissolved in Hepes buffer) at a concentration of lOOμM prevented the association of Shc/EGF-R completely, and it showed slight inhibition at 5μM compared to the negative control (P-l) (Figure 10, Panel B). P-2 dissolved in DMSO showed strong inhibition at 5 μM while P-2 at 0.5μM did not block the protein interaction (Figure 10, Panel C). Peptide localization in cells. To examine peptide localization, cells were treated with P-l or P-2 peptide for 4 hours, stained with anti-phospho-Tyr and rhodamine-conjugated antibody, and observed with a confocal microscope. A Z-scan was carried out to make images in each 0.15μm section from the top of the cells to the bottom. The image analysis of cell staining demonstrated that the P-2 peptide localized in the cytoplasm of cells, and not in the nucleus. Cells treated with P-l peptide were not stained by anti-phospho-Tyr antibody, confirming the specifity of the immunofluoroscence staining. In a time course analysis, cells were serum-starved for 24 hours, and incubated with peptide (5 μM) for various time periods. Cells were stained by anti-phosphoro-Tyr antibody and analyzed under an immunofluoroscence microscope. Cells treated with P-2 peptide retained phospho¬ peptide for up to 24 hrs . In a dose response experiment, cells were starved in serum-free medium for 24 hours, cultured with peptide at various concentrations, and stained with anti- phospho-tyrosine antibody (4G10) to detect the peptide containing phospho-tyrosine residue (red) and by Hoechst 33258 for nuclei (blue). P-2 peptide was detected at 0.5 μ M and 1 μM in cells . No signals were detected with P-l peptide in concentraions up to lμ M and weak non-specific staining was observed at 5μM. Inhibition of PTB function in vivo. Growth inhibition of cells. HER14 cells were starved for 24 hours (Figure 11, Panel a), or 48 hours (Figure 11, Panel b), treated with P-l or P-2 peptide for 2 hrs and stimulated with 1 OOng/ml EGF. Cell proliferation was measured by Η-TdR uptake (Figure 11). When cells were starved for 24 hrs, P-l and P-2 peptides slightly inhibited the proliferation of cells compared to the positive control i.e. EGF alone (a). In cells starved for 48 hrs, both peptides markedly prevented cell proliferation. In particular, about 84% inhibition was observed at 1.25μ M. Both the P-l and P-2 peptide demonstrated inhibitory activity, suggesting a non-specific effect was induced by adding peptides. The effect may be due to the internal phosphorylation of P-l peptide by activated kinase(s) after growth factor stimulation. The above experiments were repeated with cells which were serum starved for 24 hrs. Cells pretreated with P-l or P-2 did not show any decrease of cell growth rate when compared to EGF treated cells. Cells pretreated with C-2 inhibited cell growth roughly in a dose dependent manner (Figure 12). The experiment was repeated using C-l peptide as a negative control, and C-2 did not inhibit cell growth (Figure 13). A non-Hodgkin's lymphoma cell line, SupM2 was used in cell proliferation assays as described above. SupM2 has a chromosomal translocation, resulting in the expression of a fusion protein of Alk and Npm. The Alk/Npm fusion protein has a motif which is expected to be a She PTB binding domain, and the cell proliferation of SupM2 is believed to be dependent on the She pathway. SupM2 cells in the indicated cell number (Figure 14, Panel a) or at a concentration of 2 xl0 4 /well (Figure 14, Panel b), were grown in serum-free RPMI 1640 medium for 24 hr, treated with peptide for 2 hrs, then, stimulated with 20% FBS overnight, and monitored by Η-tdR pulse. P-l and P-2 peptides inhibited cell growth to background level (Figure 14), and cell proliferation was completely inhibited at 70nM. To examine the optimum dose of peptides, serial dilutions of peptides were used in the assay. At 60pM, both peptides suppressed the cell growth completely. Inhibition of PTB function in vivo. MAPK activation. The phosphorylation state of MAPK was examined after treatment with the peptides. PC 12 cells were treated with peptide, stimulated with 50ng/ml NGF, and a cell lysate was prepared. Proteins were resolved on acrylamide gel to separate phosphorylated- and non- phosphorylated MAPK. Erk-1 was detected by Western blotting. Figure 15, Panel a shows the series of samples treated with P-l or P-2, and Panel b shows the samples treated with C-l or C-2. When cells were treated with NGF, the bands expected for Erk-1 and Erk-2 were slightly shifted and showed higher molecular weights, demonstrating phosphorylation of Erk-1 and Erk-2. However, no inhibition was detected in the group treated with P-2 or C-2. To confirm this result, cell lysates of PC 12 described above were immunoprecipitated with anti-Erk-1 antibody, and the proteins were detected by anti-phospho-Tyr antibody (Figure 16). In Figure 16, Panel a shows samples treated with P-l or P-2, and Panel b shows samples treated with C-l or C-2. Two major bands were detected with predicted molecular weights of about 47kDa and about 42kDa, respectively. A weak band of 47kDa was detected in a sample treated with preimmune serum. Therefore, pp47 appeared to be a non-specific protein whereas pp42 is phosphorylated Erk-1. No differences in phosphorylation state of Erk-1 were observed among the groups treated with the peptides. The above described experiment was repeated using 3T3Trk cells stimulated with NGF. The results were similar to that obtained with PC 12 cells. No specific inhibition of Erk-1 and Erk-2 phosphorylation by C-2 or P-2 was observed. In summary, the efficacy of the peptides in Table 2 were assayed for the ability to inhibit the interaction between the She PTB domain and growth factor receptors. P-2 and C-2 peptides demonstrated strong inhibitory activities in in vitro binding assays. P-2 was found to localize in the cell cytoplasm by simply adding the peptide into the culture medium. In preliminary experiments, specific inhibition of cell growth or of MAPK activation by the peptides was not demonstrated in vivo. However, the in vivo assay system requires further optimization. Having illustrated and described the principles of the invention in a preferred embodiment, it should be appreciated to those skilled in the art that the invention can be modified in arrangement and detail without departure from such principles. We claim all modifications coming within the scope of the following claims. All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incoφorated by reference in its entirety. Below full citations are set out for the references referred to in the specification is a listing and detailed legends for the figures are provided. 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Lauris, T. J. Dull, A. Ullrich and C. R. Kahn (1988) Cell, 54, 641-649. K. Yokote, S. Mori, K. Hansen, J. McGlade, T. Pawson, C. H. Heldin and W. L. Claesson (1994) J. Biol. Chem., 269, 15337-15343. K. Yonezawa, A. Ando, Y. Kaburagi, R. Yamamoto-Honda, T. Kitamura, K. Hara, M. Nakafuku, Y. Okabayashi, T. Kadowaki, Y. Kaziro and M. Kasuga (1994) J. Biol Chem., 269, 4634-4640. Damen, J.E. et al., Proc. Natl. Acad Sci. U.S.A. 93(4), 1689-1693, 1996. DETAILED FIGURE LEGENDS Figure IA and Figure IB. The Asn present within the Asn-Pro-X-P.Tyr motif is essential for binding to the PTB domain. Figure IA. GST (lane 2) and GST She PTB (lanes 1, 3-6) fusion proteins bound to glutathione-agarose were incubated with NGF receptors present in lysates from control (lane 1) and NGF-stimulated (lanes 2-7) cells in the absence (lane 1-3) and presence of Wt (lane 4) and mutant (lanes 5 and 6) competing P.Tyr containing peptides, based on the sequence around Tyr 490 the She PTB domain binding site in the NGF receptor. Bound proteins were analyzed by anti-P.Tyr immunob lotting. Competing peptides, Wt NGF receptor (Wt NGFR): His-Ile-Ile-Glu-Asn- Pro-Gln-P.Tyr-Phe-Ser-Asp (lane 4); NGF receptor Asn(-3)Ala (NGFR Ala -3) mutant: His-Ile-Ile-Glu-Ala-Pro-Gln-P.Tyr-Phe-Ser-Asp (lane 5); NGF receptor Pro(-2)Ala (NGFR Pro -2): His-Ile-Ile-Glu-Asn-Ala-Gln-P.Tyr-Phe-Ser-Asp (lane 6). Figure IB. The blot shown under A was stripped and reprobed with an antiserum raised against the NGF receptor. Figure 2. Substitution of either the Asn or the Pro in the PTB-binding site affects its ability to bind to the PTB domain. Surface plasmon resonance technology was used to test the ability of Wt and mutant phosphopeptides, based on the sequence around Tyr 490 the She-binding site in the NGF receptor for their ability to compete for binding of the Gst- Shc PTB domain fusion protein to the immobilized polyoma middle T antigen peptide (L-S- L-L-S-N-P-T-P.Y-S-V-M-R-S-K). Wt, H-I-I-E-N-P-Q-P.Y-F-S-D: (A); Ala -3, H-I-I-E-A- P-Q-P.Y-F-S-D:( o ); Ala -2, H-I-I-E-N-A-Q-P.Y-F-S-DP( • ). Figure 3. Presence of a Asn-Pro-X-P.Tyr motif in the juxta membrane domains of the NGF and insulin receptors. Both the NGF receptor and the insulin receptor contain an autophosphorylation site within an Asn-Pro-X-P.Tyr motif in the juxta membrane domain, between the membrane and the kinase domain. In both receptors the tyrosine residues within these motif become phosphorylated upon receptor activation, but in contrast to the NGF receptor, the insulin receptor lacks the ability to stably associate with She. Figure 4A and Figure 4B. The She PTB domain does not stably bind to the Asn-Pro- X-P.Tyr motif in the insulin receptor. Figure 4A. Anti-She immunoprecipitates (lanes 1, 2, 5, 6, 9, and 10) from control (lanes 1, 5, and 9) and growth factor-stimulated (lanes 2, 6, and 10) NIH3T3 fibroblasts expressing Wt (lanes 1 and 2; NGFR) or Phe 490 mutant (lanes 5 and 6; F490NGFR) NGF receptors, or CHO cells expressing Wt insulin receptors (lanes 9 and 10; IR) were analyzed by anti-P.Tyr immunoblotting. Anti-NGF receptor (lanes 3, 4, 7, and 8) and anti-insulin receptor immunoprecipitates (lanes 11 and 12) from control (lanes 3, 7, and 11) and growth factor stimulated (lanes 4, 8, and 12) were analyzed in parallel. Figure 4B. Wt (lanes 1 and 2) and Phe 490 mutant (5 and 6) NGF receptors present in lysates from control (lanes 1 and 5) and NGF-stimulated (lanes 2 and 6) cells expressing Wt (NGFR) or Phe 490 mutant (F490NGFR) and insulin receptors (IR) present in lysates from control (lane 9) and insulin-stimulated (lane 10) cells were incubated with GST-Shc PTB fusion proteins bound to glutathione-agarose. Bound proteins were analyzed by anti-P.Tyr immunoblotting. Anti-NGF receptor immunoprecipitates (lanes 3, 4, 7, and 8) and anti-insulin receptor immunoprecipitates (lanes 11 and 12) from control (lanes 3, 7, and 11) and growth factor-stimulated (lanes 4, 8, and 12) cells were analyzed in parallel. Figure 5A and Figure 5B. An aliphatic residue five or six amino acids amino-terminal to the P.Tyr is an important determinant for She PTB binding. Figure 5A. GST-Shc PTB domain fusion proteins bound to glutathione-agarose were incubated with activated NGF receptors present in lysates of NGF-stimulated cells in the absence (lane 1) or presence (lanes 2-7) of 2μM competing Wt and mutant phosphotyrosine containing peptides based on the sequence around Tyr 490, the She PTB domain binding site in the NGF receptor (lanes 2-5) or Tyr 960 an autophosphorylation site present within an Asn-Pro-X-P.Tyr motif in the insulin receptor (lanes 6 and 7). Wt NGF receptor peptide (Wt-NGFR, lane 2): H-I-I- E-N-P-Q-p.Y-F-S-D; Ala-6 NGF receptor peptide (NGFR-HAI): H-A-I-E-N-P-Q-p.Y-F-S- D; Ala-6, Ala-5 NGF receptor peptide (NGFR-HAA): H-A-A-E-N-P-Q-p. Y-F-S-D; Ala-6, Ser-5 NGF receptor peptide (NGFR-HAS): H-A-S-E-N-P-Q-p.Y-F-S-D; Wt insulin receptor peptide (Wt-IR): Y-A-S-S-N-P-E-p.Y-L-S-A; Ile-5 insulin receptor peptide (IR- YAI): Y-A-I-S-N-P-E-p.Y-L-S-A. Bound proteins were analyzed by P.Tyr. blotting. Figure 5B. Phosphopeptides based on the sequence around Tyr 490, the She-binding site in the NGF receptor (H-I-I-E-N-P-Q-p.Y-F-S-D(»)) or Tyr 960 in the insulin receptor (Y-A-S-S- N-P-E-p.Y-L-S-A (O)) and substitutions at position -5 and -6 with respect to the P.Tyr in the NGF receptor peptides (H-A-S-E-N-P-Q-p.Y-F-S-D(>)) and the insulin receptor peptide (Y-A-I-S-N-P-E-p.Y-L-S-A(A)) were tested by surface plasmon resonance analysis technology for their ability to compete for the binding of the GST-Shc PTB domain to the immobilized polyoma middle T antigen peptide (L-S-L-L-S-N-P-T-p. Y-S-V-M-R-S-K). Figure 6A and Figure 6B. The requirement for an Arg residue at position 175 in the human She PTB domain has been conserved in evolution. Figure 6A. GST fusion proteins containing Wt (lanes 1 and 2) or mutant (lanes 3-11) She PTB domains were incubated with NGF receptors present in lysates of control (lane 1) and NGF-stimulated cells (lanes 2-11). Bound proteins were analyzed by anti-P.Tyr blotting. Figure 6B. Human EGF receptors bound to GST fusion proteins containing Wt (lanes 1 and 2) or Met 175 (lane 3) and Lys 175 (lane 4) mutant human She PTB domains in lysates from control (lane 1) or EGF-stimulated cells (lanes 2-4) were analyzed by anti-P.Tyr blotting. In parallel GST (lane 8) and GST fusion proteins containing Wt (lane 7) or an Ala 151 mutant (lane 9) drosophila She PTB domain bound to glutathione-agarose, were incubated with fly lysates containing activated Torso-DER chimeric proteins that contain the cytoplasmic domain of DER; bound proteins were detected by anti-P.Tyr blotting. An anti-She (lane 5) and a normal rabbit serum immunoprecipitate (lane 6) from the same fly lysates are shown as controls. Figure 8. Peptides Competition in In Vitro Binding Assay. Cell Lysates were pre- incubated with 5μM of appropriate peptides for 30 min. at 4°C. Then, proteins were precipitated by each binder, resolved on SDA-PAGE. Detection was carried out by anti- phospho-tyrosine antibody. Ins.:IRS-l binding domain on insulin-R. Figure 9. Competition Assay of Penetrating Peptide. Cell lysates were pre-treated with appropriate peptides. Proteins were precipitated by GST-ShcB and detected by anti- phospho-tyrosine antibody. Peptides were prepared in DMSO solution. Figure 10. Dose-Response Analysis of Peptides in in vitro Binding Assay. Cell Lysates were prepared and incubated with appropriate peptides in various concentrations. Proteins were precipitated by GST-ShcB and resolved on 10% SDS-PAGE gel. Anti-phospho- tyrosine antibody was used for detection. P-l and P-2 peptides were dissolved in Hepes buffer (B), and in DMSO solution (C). Figure 11. Proliferation of HER14 cells treated with peptides. Cells were starved for 24 (a) or 48 hrs (b) prior to stimulation. Cells were treated with appropriate peptide for 2 hrs, then stimulated with lOOng ml EGF overnight. Cell proliferation was monitored by 3 H-TdR uptake. Figure 12. Proliferation of HER14 cells. HER14 cells were cultured in serum-free D- MEM medium in 96-well plates for 24 hrs. Appropriate peptides were added in various concentrations 2 hrs prior to EGF stimulation. Cell proliferation was induced with lOOng/ml EGF overnight, then monitored by 3 H-TdR uptake. Figure 13. Proliferation of HER14 cells treated with cyclic peptides. Cells were starved for 48 hrs in serum-free D-MEM medium. Appropriate peptide was added in various concentrations and cultured for 2 hrs prior to EGF stimulation. Cell proliferation was induced with lOOng/ml EGF overnight and monitored by 3 H-TdR uptake. Figure 14. Proliferation of SupM2 cells treated with peptides. SupM2 cells were starved in serum-free RPMI 1640 medium for 24 hrs in the indicated cell number (a) or 2xl0 4 /well (b). Cells were treated with penetrating peptide in various concentrations for 2 hrs prior to cell stimulation. Cell proliferation was induced with 20% FPS overnight and monitored by 3 H-TdR pulse. Figure 15. MAPK Activation on PC12 Cells Treated with Peptides. PC12 cells were treated with appropriate peptide at various concentrations. Cells were stimulated with 50ng/ml NGF for 5 min., then cell lysates were prepared by standard methods. Each lane contains lOμg protein and MAPK (Erk-1) was detected by anti-Erk-1 polyclonal Ab. Arrows represent activated Erk-1/2 (b). Figure 16. Detection of Activated MAPK on PC12 Cells Treated with Peptides. PC 12 cells were treated with peptides for 4 hrs prior to stimulation. Cells were stimulated with 50ng/ml NGF for 5 min. and cell lysates were prepared according to standard methods. 500μg of cell lysates were immunoprecipitated with anti-Erk-1 polyclonal antibody, and activated Erk-1 proteins were detected by Western blotting of anti-phospho-tyrosine antibody (4G10). Arrow represents activated (phosphorylated) Erk-1 and asterisk shows non-specific band. TABLE 1 Phosphotyrosine-containing peptides IC 50 H-I-I-E-N-P-Q-P.Y-F-S-D 175 nM H-I-I-E-A-P-Q-P.Y-F-S-D 80000 nM H-I-I-E-N-A-Q-P.Y-F-S-D 2500 nM H-A-I-E-N-P-Q-P.Y-F-S-D 20 nM H-I-A-E-N-P-Q-P.Y-F-S-D 250 nM H-A-A-E-N-P-Q-P.Y-F-S-D 475 nM H-A-S-E-N-P-Q-P.Y-F-S-D 15000 nM Y-A-S-S-N-P-E-P.Y-L-S-A 7000 nM Y-A-I-S-N-P-E-P.Y-L-S-A 90 nM Table 1. Peptide competition of the GST-Shc PTB domain binding to a polyoma middle T antigen phosphopeptide (L-S-L-L-S-N-P-T-P.Y-S-V-M-R-S-K). Surface plasmon resonance technology was used to evaluate the ability of phosphopeptides derived from sequences around the Tyr 490, the She binding site in the NGF receptor (H-I-I-E-N-P-Q-P.Y-F-S-D) and Tyr 960 in the insulin receptor (Y-A-S-S-N-P- E-P.Y-L-S-A) to bind to the She PTB domain. Amino acid substitutions were introduced into the peptides (shown in bold). Peptide concentrations that inhibit binding by 50% (IC50) are listed. TABLE 2 Code Amino acid sequence Trk wild type HIIENPQpYFSD 175n lENPQpYFSD 4μ 01 C clθ-(IENPQpYFSPG) C-2 CIIENPQpYFC I — ss — ' C-3 Cyclo-(NPQpY) C-4 Cyolo-(NPQpYG) C-5 Cyclo-(NPQpYGG) P-1 RQIKIWFQNRRMKWKK-HIIENPQYFSD P-2 RQiKIWFQNRRMKWKK-HIIENPQpYFSD P-3 Blotiπ-ACA-AAVALLPAVLLALLAP-HIIENPQYFSD P-4 Biotin-ACA-AAVA LPAVLLALLAP.HIIENPQpYFSD P-5 CGHIIENPQpYFSD SS- Blot In-Basic penetrating peptide (RQIKIWFQNRR KWKK?) SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANTS: NAME: Mount Sinai Hospital Corporation STREET: 600 University Avenue, Suite 970 CITY: Toronto STATE: Ontario COUNTRY: Canada POSTAL CODE: M5G 1X5 TELEPHONE NO. : (416) 586-3235 TELEFAX NO.: (416) 586-3110 NAME: Asahi Chemical Industry Co. , Ltd. STREET: Hibiya-Mitsui Bldg., 1 - 2, Yuraku-cho, 1-Chome, Chiyoda-Ku CITY: Tokyo STATE: N/A COUNTRY: Japan POSTAL CODE: N/A TELEPHONE NO. : TELEFAX NO. : NAME: van der Greer, Peter STREET: 33 Wood Street, Apt. 2204 CITY: Toronto STATE: Ontario COUNTRY: Canada POSTAL CODE (ZIP) : M4Y 2P8 NAME: Wiley, Sandra STREET: 33 Wood Street, Apt. 2204 CITY: Toronto STATE: Ontario COUNTR : Canada POSTAL CODE (ZIP) : M4Y 2P8 NAME: Gish, Gerald D. STREET: 6 Grangemill Crescent CITY: Don Mills STATE: Ontario COUNTRY: Canada POSTAL CODE (ZIP): M3B 2J2 NAME: Pawson, Tony STREET: 34 Glenwood Avenue CITY: Toronto STATE: Ontario COUNTRY: Canada POSTAL CODE (ZIP) : M6P 3C6 NAME: Toma, Kazunori STREET: 4-8-36, Yokodai CITY: Sagamihara STATE: N/A COUNTRY: Japan POSTAL CODE: ZIP 229 (ii) TITLE OF INVENTION: Peptides Which Interfere With the Interaction of a Phosphotyrosine-Binding (PTB) Domain Containing Protein With a PTB Domain Binding Site (iii) NUMBER OF SEQUENCES: 29 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: HOWSON AND HOWSON (B) STREET: Spring House Corporate Cntr., P.O. Box 457 (C) CITY: Spring House (D) STATE: Pennsylvania (E) COUNTRY: USA (F) ZIP: 19477 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: WO (B) FILING DATE: (C) CLASSIFICATION: (viii) ATTORNE /AGENT INFORMATION: (A) NAME: Kodroff, Cathy A. (B) REGISTRATION NUMBER: 33,980 (C) REFERENCE/DOCKET NUMBER: 3153-199 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (215) 540-9200 (B) TELEFAX: (215) 540-5818 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (3) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY; linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: His He He Glu Asn Pro Gin Tyr Phe Ser Aso 1 5 10 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ( i ) FEATUR : (A) NAME/KEY: Peptide (3) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tv. (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 2 : His Ala He Glu Asn Pro Gin Tyr Phe Ser Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: His He Ala Glu Asn Pro Gin Tyr Phe Ser Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 ( D ) OTHER INFORMATION : /note= " Phosphorylated at Tyr " ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 4 : He He Glu Asn Pro Gin Tyr Phe Ser Asp Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Tyr Ala He Ser Asn Pro Glu Tyr Leu Ser Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Thr Trp He Glu Asn Lys Leu Tyr Gly Met Ser Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO:7 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: Thr Trp He Glu Asn Lys Leu Tyr Gly Thr Ser Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Leu Leu Leu Ser Asn Pro Ala Tyr Arg Leu Leu Leu 1 5 10 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Tyr Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: Val Ser Val Asp Asn Pro Glu Tyr Leu Leu Asn Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: Ser Leu Leu Ser Asn Pro Thr Tyr Ser Val Met Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 : Asn Glu Met He Asn Pro Asn Tyr He Gly Met Gly 1 5 10 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..12 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Glu Met Phe Glu Asn Pro Leu Tyr Gly Ser Val Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..7 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: He Glu Asn Pro Gin Tyr Phe 1 5 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..8 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: He Glu Asn Pro Gin Tyr Phe Ser 1 5 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..7 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Ala Glu Asn Pro Gin Tyr Phe 1 5 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..8 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: He Glu Asn Pro Gin Tyr Phe Ser Pro Gly 1 5 10 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..7 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: He Ser Asn Pro Glu Tyr Leu 1 5 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..11 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Val Leu Ala Asp Asn Pro Ala Tyr Arg Ser Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..14 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: Ala Leu Leu Leu Ser Asn Pro Ala Tyr Arg Leu Leu Leu Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..18 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr 11" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Gly Pro Leu Tyr Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser Asp 1 5 10 15 Val Phe (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..15 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Pro Val Ser Val Asp Asn Pro Glu Tyr Leu Leu Asn Ala Gin Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..15 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: Leu Ser Leu Leu Ser Asn Pro Thr Tyr Ser Val Met Arg Ser Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..18 ( D) OTHER INFORMATION : /note= " Phosphorylated at Tyr " (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 24 : Val Ser Ser Leu Asn Glu Met He Asn Pro Asn Tyr He Gly Met Gly 1 5 10 15 Pro Phe (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: unknown (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..20 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: Leu Leu Leu Thr Lys Pro Glu Met Phe Glu Asn Pro Leu Tyr Gly Ser 1 5 10 15 Val Ser Ser Phe 20 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "cyclic" (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..10 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: He Glu Asn Pro Gin Tyr Phe Ser Pro Gly 1 5 10 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "cyclic" (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..13 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: He He Glu Asn Pro Gin Tyr Phe Ser Asp Ala Pro Gly 1 5 10 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "cyclic" ( ix) FEATURE : (A) NAME/KEY: Peptide (B) LOCATION: 1..14 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: His He He Glu Asn Pro Gin Tyr Phe Ser Asp Ala Pro Gly 1 5 10 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "cyclic" (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 1..10 (D) OTHER INFORMATION: /note= "Phosphorylated at Tyr" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Cys He He Glu Asn Pro Gin Tyr Phe Cys 1 5 10

Claims: WE CLAIM 1. A peptide of the formula I Xi - Ai - A2 - X2 - Asn - X3 - X4 - P.Tyr - X5 - X6 - χ7- χ8 I wherein Xi represents Lys, Arg, His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, A' represents Tφ, Leu, Ala, Ser, He, Glu, Met, Gly, Cys, Phe, Pro, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, Phe, Gly, Cys, Trp, or Pro, X2 represents Glu, Asn, Tyr, Thr, Ser, Asp, or He, X3 represents Pro, Met, Trp, Phe, Ala, Lys, Val, Leu, He, Gly, or Cys, X 4 represents Leu, Ala, Glu, Gin, Asp, Asn, Tyr, Thr, or Ser, X5 represents Phe, Trp, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Arg or Ser, X6 represents Ser, Thr, Tyr, Asn, Glu, Met, Ala, Leu, Val, or Gly, X? represents Asp, Glu, Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, Ser, or Asn, and X8 which may be present or absent, represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, Asp, Ser, or Arg, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. 2. A peptide of the formula I as claimed in claim 1, wherein X ' represents His, Ser, Thr, Tyr, Asn, Leu, Val, or Glu, X 2 represents Glu, Ser, Asp, or He, X3 represents Pro or Lys, X 4 represents Leu, Ala, Glu, Gin, Asn, or Thr, X5 represents Phe, Leu, He, Gly, Arg, or Ser, X6 represents Ser, Thr, Met, Ala, Leu, Val, or Gly, X 7 represents Asp, Ala, Val, Leu, Met, Ser, or Asn, X8 which may be present or absent, represents Leu, Ala, Gly, Asp, Ser, or Arg, Al represents Tφ, Leu, Ala, Ser, He, Glu, Met, or Val, and A 2 represents Ala, Val, Leu, He, Ser, Met, or Phe, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. 3. A peptide of the formula Ia Xi - Al - A2 - X2. Asn - X3 - X 4 - P.Tyr - X5 - X6 - χ7 i a wherein X i represents Lys, Arg, His, preferably His, X 2 represents Glu, Asn, Tyr, Thr, Ser, preferably Glu, X 3 represents Pro, Met, Tφ, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Gin, Asp, Asn, Tyr, Thr, Ser, preferably Gin, X 5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met, preferably Phe, X 6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Asp, Glu, preferably Asp, and one of A i and A2 represents He and the other of A ' and A 2 represents He or Ala, preferably A 1 represents Ala and A 2 represents He, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. 4. A peptide of the formula Ia Xi - Al - A 2 - X2. Asn - X3 - X 4 - P.Tyr - X5 - X6 - X? ι a wherein X 1 represents Ser, Thr, Tyr, Asn or Glu, preferably Tyr, X2 represents Glu, Asn, Tyr, Thr, Ser, preferably Ser, X 3 represents Pro, Met, Tφ, Phe, Ala, Val, Leu, He, Gly, Cys, preferably Pro, X 4 represents Glu, Asp, preferably Glu, X5 represents Phe, Tφ, Pro, Leu, Ala, Val, He, Gly, Cys, Met preferably Leu, X6 represents Ser, Thr, Tyr, Asn, Glu, preferably Ser, X 7 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met, Pro, preferably Ala, and one of A 1 and A 2 represents He and the other of A i and A 2 represents Ala, Val, Leu, He, Gly, Cys, Phe, Tφ, Met or Pro, which interferes with the interaction of a PTB domain containing protein with a PTB domain binding site. 5. A peptide consisting of the sequence His-Ile-He-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser- Asp ; His- Ala-Ile-Glu- Asn-Pro-Gln-P.Tyr-Phe-Ser- Asp ; His-Ile- Ala-Glu- Asn-Pro-Gln- P.Tyr-Phe-Ser-Asp; Ile-Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser-Asp-Ala; Tyr-Ala-Ile-Ser- Asn-Pro-Glu-P.Tyr-Leu-Ser-Ala; Thr-Tφ-Ile-Glu-Thr-Tφ-Ile-Glu-Asn-Lys-Leu-P.Tyr- Gly-Met-Ser-Asp; Thr-Tφ-Ile-Glu-Thr-Tφ-Ile-Glu-Asn-Lys-Leu-P.Tyr-Gly-Thr-Ser- Asp; Leu-Leu-Leu-Ser-Asn-Pro-Ala-P.Tyr.-Arg-Leu-Leu-Leu; Tyr-Ala-Ser-Ser-Asn-Pro- Glu-P.Tyr-Leu-Ser-Ala-Ser; Val-Ser-Val-Asp-Asn-Pro-Glu-P.Tyr-Leu-Leu-Asn-Ala; Ser- Leu-Leu-Ser-Asn-Pro-Thr-P.Tyr-Ser-Val-Met-Arg; Asn-Glu-Met-He-Asn-Pro-Asn-P.Tyr- Ile-Gly-Met-Gly; Glu-Met-Phe-Glu-Asn-Pro-Leu-P.Tyr-Gly-Ser-Val-Ser; Ile-Glu-Asn- Pro-GIn-P.Tyr-Phe; Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser; Ala-Glu-Asn-Pro-Gln-P.Tyr- Phe; Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser; Ile-Ser-Asn-Pro-Glu-P.Tyr-Leu; or Val-Leu- Ala-Asp-Asn-Pro-Ala-P.Tyr-Arg-Ser-Ala (SEQ. ID. NOs. 1 to 19 in the Sequence Listing). 6. A peptide consisting of the sequence Ala-Leu-Leu-Leu-Ser-Asn-Pro-Ala-P.Tyr.- Arg-Leu-Leu-Leu-Ala; Gly-Pro-Leu-Tyr-Ala-Ser-Ser-Asn-Pro-Glu-P.Tyr-Leu-Ser-Ala- Ser-Asp-Val-Phe; Pro-Val-Ser-Val-Asp-Asn-Pro-Glu-P.Tyr-Leu-Leu-Asn-Ala-Gln-Lys; Leu-Ser-Leu-Leu-Ser-Asn-Pro-Thr-P.Tyr-Ser-Val-Met-Arg-Ser-Lys; Val-Ser-Ser-Leu- Asn-Glu-Met-Ile-Asn-Pro-Asn-P.Tyr-Ile-Gly-Met-Gly-Pro-Phe; or Leu-Leu-Leu-Thr- Lys-Pro-Glu-Met-Phe-Glu-Asn-Pro-Leu-P.Tyr-Gly-Ser-Val-Ser-Ser-Phe (SEQ. ID. NOs. 20 to 25 in the Sequence Listing). 7. Cyclo-(Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Ser-Pro-Gly, cyclo-(Ile-Ile-Glu-Asn- Pro-Gln-P.Tyr-Phe-Ser-Asp-Ala-Pro-Gly), cyclo-(His-Ile-Ile-Glu-Asn-Pro-Gln-P.Tyr- Phe-Ser-Asp-Ala-Pro-Gly) or Cys-Ile-Ile-Glu-Asn-Pro-Gln-P.Tyr-Phe-Cys (SEQ. ID. NOs. 26 to 29 . 8. Use of a peptide of the formula I as claimed in claim 1 for interfering with the interaction of a PTB domain containing protein with a PTB domain binding site. 9. A pharmaceutical composition for inhibiting the interaction of a PTB domain with a phosphotyrosine-containing protein comprising a peptide as claimed in claim 1 and a pharmaceutically acceptable carrier.

Inventors: GISH GERALD, PAWSON TONY, TOMA KAZUNORI, VAN DER GEER PETER, WILEY SANDRA, GISH, GERALD, PAWSON, TONY, TOMA, KAZUNORI, VAN DER GEER, PETER, WILEY, SANDRA
Applicants: ASAHI CHEMICAL IND, GEER PETER V D, GISH GERALD, MOUNT SINAI HOSPITAL CORP, PAWSON TONY, TOMA KAZUNORI, WILEY SANDRA, ASAHI CHEMICAL INDUSTRY CO., LTD., GISH, GERALD, MOUNT SINAI HOSPITAL CORPORATION, PAWSON, TONY, TOMA, KAZUNORI, VAN DER GEER, PETER, WILEY, SANDRA
Application year: 1996
Main classification: A61K38
IPC codes: A61K31, A61K38, A61P3, A61P13, A61P29, A61P31, A61P35, A61P37, A61P43, C07K7, C07K14