Signal Transduction Pathways That Regulate Eukaryotic Protein Synthesis (1999)

eukaryotic initiation factor amino acids adenylate cyclase calmodulin diacylglycerol eukaryotic elongation factor eEF2 kinase epidermal growth factor extracellular signal-regulated kinase guanine nucleotide exchange factor G-protein-coupled receptors glycogen synthase kinase-3 inositol insulin receptor substrate mitogen-activated protein kinase mitogen-activated protein/ERK kinase MAPK-interacting kinase mammalian target of rapamycin 70-kDa ribosomal S6 kinase 90-kDa ribosomal S6 kinase PtdIns-dependent kinase pleckstrin homology phosphorylated, heat- and acid-stable protein phosphatidylinositol 3-kinase protein kinase B protein kinase C phospholipase C phosphatidylinositol receptor kinase substrates receptor tyrosine kinase Src homology domain 2 SH2-containing phosphotyrosine phosphatase-2 terminal oligopyrimidine untranslated region The last several years have witnessed an explosion in the published literature on two topics, the pathways that transduce extracellular signals to their intracellular targets and modification of the core translational apparatus in response to these signals. Most of these pathways result in cell growth and cell division. Synthesis of the entire complement of proteins is necessary to double the cell size, but synthesis of the so-called "growth-regulated" proteins (1Baserga R. Cancer Res. 1990; 50: 6769-6771PubMed Google Scholar) is needed for cell division. This article summarizes recent advances in our understanding of how a single mitogenic stimulus can simultaneously lead to an increase in both global and growth-regulated protein synthesis. The three stages of protein synthesis are catalyzed by initiation, elongation, and release factors (Ref. 2Merrick W.C. Hershey J.W.B. Hershey J.W.B. Mathews M.B. Sonenberg N. Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1996: 31-69Google Scholar; a guide to current and previous nomenclature can be found in Ref. 3Clark B.F.C. Grunberg-Manago M. Gupta N.K. Hershey J.W.B. Hinnebusch A.G. Jackson R.J. Maitra U. Mathews M.B. Merrick W.C. Rhoads R.E. Sonenberg N. Spremulli L. Trachsel H. Voorma H.O. Biochimie ( Paris ). 1996; 78: 11-12Crossref Scopus (41) Google Scholar). A ternary complex of eIF2·GTP·Met-tRNAi1 binds to the 40 S ribosomal subunit to form the 43 S initiation complex (Fig.1). The eIF4 factors plus poly(A)-binding protein recognize the 5′-terminal cap or 3′-terminal poly(A) tract of mRNA, unwind mRNA secondary structure, and transfer it to the 43 S initiation complex, resulting in the 48 S initiation complex. Scanning for the first initiation codon in good sequence context requires eIF4A and the presence of eIF1 and eIF1A (4Pestova T.V. Borukhov S.I. Hellen C.U.T. Nature. 1998; 394: 854-859Crossref PubMed Scopus (320) Google Scholar). Then eIF5 stimulates GTP hydrolysis by eIF2, after which the initiation factors are replaced by the 60 S subunit to form the 80 S initiation complex. The released eIF2·GDP is recycled to eIF2·GTP by the GEF eIF2B. The first elongator aminoacyl-tRNA is brought to the A-site by eEF1, followed by a cycle of GTP hydrolysis and exchange analogous to that of eIF2. Translocation is catalyzed by eEF2, again with a GTP hydrolysis cycle. The binding of growth factors to the extracellular domain of RTKs causes a conformational change that induces oligomerization and activation of the intracellular protein Tyr kinase domain (Ref. 5Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4245) Google Scholar; Fig. 2). Substrates for the kinase can be either the RTK itself or a separate RKS. The SH2 domains of several different signaling molecules dock to the resulting Tyr(P)s in a sequence-specific manner, thereby activating separate downstream signaling cascades. These receptors are coupled to heterotrimeric G-proteins (6Vaughan M. J. Biol. Chem. 1998; 273: 17297Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Dissociation of the G-protein subunits activates AC, PLC, and other downstream effectors. PLC hydrolyzes PtdIns(4,5)P2 to DAG and Ins(1,4,5)P3. These are docking proteins for downstream effectors of RTKs (7White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (625) Google Scholar). The best studied RKS are the insulin receptor substrates, which include IRS-1, IRS-2, IRS-3, Gab-1, and p62DOK. Members of the IRS family bind to insulin receptor via an NH2-terminal PH domain and a Tyr(P)-binding domain. The COOH-terminal portions of the proteins contain numerous Tyr phosphorylation sites. IRS-1 alone provides docking sites for PI3-K, SH-PTP2, Grb-2, Fyn, Nck, and Crk. This phosphatase contains two SH2 domains, and enzyme activity is maximally activated when both are occupied by Tyr(P)-containing peptides (8Pluskey S. Wandless T.J. Walsh C.T. Shoelson S.E. J. Biol. Chem. 1995; 270: 2897-2900Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). SH-PTP2 is activated by docking to EGF receptor, platelet-derived growth factor receptor, c-kit, insulin receptor, IRS-1, IRS-2, and IRS-3 and may serve to attenuate the Tyr(P) signal in these molecules (7White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (625) Google Scholar). This G-protein is bound to the plasma membrane by COOH-terminal prenylation and myristoylation (9Vojtek A.B. Der C.J. J. Biol. Chem. 1998; 273: 19925-19928Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). GEF activity is provided by SOS, which associates constitutively with the SH2- and SH3-containing protein Grb-2. The Grb-2·SOS complex is recruited to the plasma membrane by binding to specific Tyr(P)s in IRS-1, IRS-2, Shc, or SH-PTP2 (7White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (625) Google Scholar). Another GEF, Ras-GEF, is stimulated by Ca2+/calmodulin (CaM) downstream of GPCR (10Downward J. Nature. 1998; 396: 416-417Crossref PubMed Scopus (36) Google Scholar). The hydrolysis of GTP by Ras is stimulated by GTPase-activating proteins such as p120GAP and NF1 (9Vojtek A.B. Der C.J. J. Biol. Chem. 1998; 273: 19925-19928Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). Ras·GTP activates the Ser/Thr kinase Raf-1 by recruiting it to the plasma membrane. Raf-1, in turn, phosphorylates and activates MEK1 and MEK2. The MEKs are dual specificity kinases, phosphorylating both Thr and Tyr residues in ERK1 and ERK2 (p42 and p44 MAPKs). This kinase is composed of a catalytic subunit and a SH2-containing regulatory subunit that binds to Tyr(P)s in RTKs and RKS (7White M.F. Mol. Cell. Biochem. 1998; 182: 3-11Crossref PubMed Scopus (625) Google Scholar). PI3-K is also activated synergistically by direct binding to Ras·GTP (11Rodriguez-Viciana P. Warne P.H. Vanhaesebroeck B. Waterfield M.D. Downward J. EMBO J. 1996; 15: 2442-2451Crossref PubMed Scopus (501) Google Scholar). PI3-K is a dual specificity kinase that phosphorylates PtdIns at the 3-position and proteins on Ser/Thr residues (12Divecha N. Irvine R.F. Cell. 1995; 80: 269-278Abstract Full Text PDF PubMed Scopus (590) Google Scholar). The lipid phosphorylation signal activates PDK and PKB, and the protein phosphorylation signal activates MAPK (13Bondeva T. Pirola L. Bulgarelli-Leva G. Rubio I. Wetzker R. Wymann M.P. Science. 1998; 282: 293-296Crossref PubMed Scopus (302) Google Scholar). Both activities are inhibited by wortmannin and LY294002 (14Vlahos C.J. Matter W.F. Hui K.Y. Brown R.F. J. Biol. Chem. 1994; 269: 5241-5248Abstract Full Text PDF PubMed Google Scholar). These recently discovered kinases, with at least four isoforms, bind to and are activated by PtdIns(3,4,5)P3 by their COOH-terminal PH domains (15Stokoe D. Stephens L. Copeland T. Gaffney R.J. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1054) Google Scholar, 16Stephens L. Anderson K. Stokoe D. Erdjument-Bromage H. Painter G.F. Holmes A.B. Gaffney R.J. Reese C.B. McCormick F. Tempst P. Coadwell J. Hawkins P.T. Science. 1998; 279: 710-714Crossref PubMed Scopus (916) Google Scholar). PKB exists in at least four isoforms (α, β1, β2, γ) and is activated by both RTKs and GPCR. In the former case, PI3-K is involved (17Wijkander J. Holst L.S. Rahn T. Resjo S. Castan I. Manganiello V. Belfrage P. Degerman E. J. Biol. Chem. 1997; 272: 21520-21526Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), but in the latter, there are both PI3-K-dependent (18Murga C. Laguinge L. Wetzker R. Cuadrado A. Gutkind J.S. J. Biol. Chem. 1998; 273: 19080-19085Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar) and -independent (19Moule S.K. Welsh G.I. Edgell N.J. Foulstone E.J. Proud C.G. Denton R.M. J. Biol. Chem. 1997; 272: 7713-7719Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar) pathways. PKB is targeted to the plasma membrane by direct binding to PtdIns(3,4)P2 and PtdIns(3,4,5)P3 through its PH domain (20Sable C.L. Filippa N. Filloux C. Hemmings B.A. Obberghen E.V. J. Biol. Chem. 1998; 273: 29600-29606Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), where it is activated by phosphorylation at Thr-308 by PDK (15Stokoe D. Stephens L. Copeland T. Gaffney R.J. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1054) Google Scholar). There are at least 10 isoforms of PKC (α–ζ) that differ in responsiveness to phospholipids and Ca2+ (21Dekker L.V. Parker P.J. Trends Biochem. Sci. 1994; 19: 73-77Abstract Full Text PDF PubMed Scopus (920) Google Scholar). 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Sci. 1997; Full Text PDF PubMed Scopus Google Scholar). isoforms have and F. H. S. Sonenberg N. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Phosphorylation of occurs at or two to of which to result from direct phosphorylation by mTOR (34Burnett P.E. Barrow R.K. Cohen N.A. Snyder S.H. Sabatini D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1432-1437Crossref PubMed Scopus (947) Google G.J. A. H. P.J. Lawrence J.C. R.T. Science. 1997; 277: PubMed Scopus Google Scholar). These kinases, to as binding of ERK1 and -2 A. Proud C.G. J.A. EMBO J. 1997; PubMed Scopus Google Scholar) and in a for ERK1 substrates R. T. EMBO J. 1997; PubMed Scopus Google Scholar). is activated by phosphorylation at and both by a mitogen-activated pathway via ERK1 or -2 and also by a pathway via J.C. B. M. J.A. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). also binds to the of J.C. B. M. J.A. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google S. H. R. T. Sonenberg N. 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This GEF is phosphorylated on the subunit and by and G.I. S. B. Proud C.G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Phosphorylation occurs at that a phosphorylation at by other kinase is needed G.I. Foulstone E.J. Proud C.G. Biochem. 1997; Scopus Google Scholar). The mRNA protein is phosphorylated at in vivo B. R. J. R. E. Rhoads R.E. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Proud C.G. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar) by and -2 A. Proud C.G. J.A. EMBO J. 1997; PubMed Scopus Google Scholar, J.C. B. M. J.A. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar), resulting in an increase of its for M.L. Rhoads R.E. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). to bind are phosphorylated S. H. R. T. Sonenberg N. EMBO J. 1999; PubMed Scopus Google Scholar). The of is also by of an complex with and phosphorylation of causes of the complex T. A. G. Sonenberg N. Lawrence J.C. Science. 1994; PubMed Scopus Google Scholar, A. G.J. A. T. Lawrence J.C. Sonenberg N. Nature. 1994; PubMed Scopus Google Scholar). The these two regulatory mechanisms is In phosphorylation by A. J.A. Proud C.G. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), but in is phosphorylated in that phosphorylation is of J.C. B. M. J.A. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). This as of the complex, is phosphorylated at sites by S6 kinase D. Traugh J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The phosphorylated complex is for in synthesis and binding of mRNA to the 43 S initiation complex. This ribosomal protein is phosphorylated at at and (33Proud C.G. Trends Biochem. Sci. 1996; 21: 181-185Abstract Full Text PDF PubMed Scopus (199) Google Scholar). the of S6 phosphorylation on protein synthesis is There is a activation of p70S6K and of a tract Fumagalli S. Dennis P.B. C. Thomas G. 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Biochem. PubMed Scopus Google Scholar). by the best of protein stimulates both initiation and phosphorylation but activity by the pathway IRS-1 and Ref. R. White M.F. Rhoads R.E. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar) PI3-K R. White M.F. Rhoads R.E. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar) PDK PKB T. H. Y. S. M. M. T. H. U. M. Mol. Cell. Biol. 1998; PubMed Scopus (296) Google Scholar) GSK-3 (28Hajduch E. Alessi D.R. Hemmings B.A. Hundal H.S. Diabetes. 1998; 47: 1006-1013Crossref PubMed Scopus (296) Google Scholar) G.I. Foulstone E.J. Proud C.G. Biochem. 1997; Scopus Google Scholar) Fig. 2). insulin may through constitutively active PKCζ stimulates protein synthesis in an activating that PKB is involved R. Kollmorgen G. White M.F. Rhoads R.E. Mol. Cell. Biol. 1997; 17: 5184-5192Crossref PubMed Google Scholar). of SH-PTP2 to and insulin-stimulated protein synthesis R. P. Rhoads R. White J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). PHAS-I is phosphorylated in response to insulin A. G.J. A. T. Lawrence J.C. Sonenberg N. Nature. 1994; PubMed Scopus Google Scholar, T. A. G. Sonenberg N. Lawrence J.C. Science. 1994; PubMed Scopus Google Scholar) through a rapamycin-sensitive but pathway R. White M.F. Rhoads R.E. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, I. Lawrence J.C. J. Biol. Chem. 1996; Full Text Full Text PDF Scopus Google Scholar, Sonenberg N. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar) that PKB Sonenberg N. N. 1998; PubMed Scopus Google Scholar), that the pathway is IRS-1 and PI3-K PDK PKB mTOR Phosphorylation of is by the pathway IRS-1 Grb-2·SOS Ras are numerous other RKS that to insulin of with is stimulated by insulin S. M. G. D. L.S. J. J. 1999; Scholar) as is phosphorylation D. Traugh J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). 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