T cell antigen receptor signal transduction: A tale of tails and cytoplasmic protein-tyrosine kinases

The mechanisms by which extracellular ligands induce receptor-regulated signal transduction events have been an area of intense investigation. Remarkable progress has been made in understanding howthe binding of extracellular ligands to protein-tyrosine kinase (PTK) growth factor receptors induces the activation of their kinase domains. In contrast, the mechanism whereby receptors without an intrinsic PTK domain activate cytoplasmic PTKs has been enigmatic. However, recent studies of receptors involved in antigen recognition by cells of the hematopoietic lineage provide insight into functionally important cytoplasmic sequence motifs of these receptors and the interaction of these motifs with cytoplasmic PTKs of the Src and non-Src types. This review focuses on mechanisms involved in PTK activation by the T cell antigen receptor (TCR), but similar mechanisms are likely to be relevant for the B cell antigen receptor, the mast cell and basophil high affinity Fc receptorfor immunoglobulin (lg) E (FcsR), and certain Fc receptors expressed on natural killer (NK) cells and myeloid cells. These receptors are involved in the initiation of cellular activation or differentiation but are not directly involved in cell proliferation. All of these receptors, which are responsible for antigen recognition, initiate cellular activation by regulating the function of cytoplasmic PTKs that control the activation of intracellular signaling molecules, such as phospholipase C (reviewed by Samelson and Klausner, 1992). Act/vat/on Motifs in the TCR CD3 and 4 Chains Regulate Cytoplasmic PTKs The TCR is a complex oligomer composed of the products of six genes (Figure l), all of which are required for efficient plasma membrane expression. Together, the a and 8 chains form the ligand-binding subunit responsible for recognition of an antigenic peptide bound to a major histocompatibility complex (MHC) molecule. The CD3 and 5 chains are responsible for signal transduction. Recent studies with chimeric molecules and reconstituted receptors have provided definitive evidence for a signal transduction function for the CD3 and c chains. The transmembrane and membrane-proximal segments of the TCR chains are responsible for the interchain associations and the assembly of the oligomeric receptor. This observation permitted the development of a strategy to study the functions of the individual cytoplasmic domains of CD3 or r;. Chimeric molecules containing the cytoplasmic domain of 6, its alternatively spliced product n, or the related FCER y chains fused to the extracellular and transmembrane domains of another receptor (including CD8, CD4, CD18, and the interleukin-2 [IL-21 receptor a chain) could be expressed independently of theTCR (Irving and Weiss, 1991; Letourneur and Klausner, 1991; Romeo and Seed, 1991). Stimulation of these chimeric receptors with natural ligands or monoclonal antibodies (MAbs) induce all the early and late events characteristically associated with the intact oligomeric TCR. These findings suggest that 1; or the related chains can function to couple the TCR to intracellular signal transduction machinery. Surprisingly, subsequent experiments suggested a similar function for the CD3 chains. Reconstitution of TCR expression on a T cell hybridoma with cDNAs encoding various TCR chains has revealed that a funcfionally active TCR can be restored with a r; chain that is essentially devoid of cytoplasmic sequences (Wegener et al., 1992). A signaling function for the CD3 chains was confirmed when a chimeric molecule incorporating the CD3 E chain cytoplasmic domain was shown to be capable of activating a T cell hybridoma (Letourneur and Klausner, 1992). Thus, the CD3 and r; chains, though structurally distinct, appear to have redundant functions in TCR signaling. Identification of the functional domains of the chimeric receptors (Irving et al., 1993; Letourneur and Klausner, 1992; Romeo et al., 1992) explained the redundancy of function of the CD3 and r; chains. A sequence motif, first noted by Reth (1989), which is triplicated in 5 and present as a single copy in each of the CD3 chains, is responsible for the signal transduction capability of these chains (Figures 1 and 2). This motif, referred to herein as the antigen recognition activation motif (ARAM), is based on tyrosine and leucine (or isoleucine) residues. ARAMs are also present in the cytoplasmic domains of the proteins (Iga and lgp) associated with immunoglobulin on B cells, the 8 and y chains of the FcsR on mast cells and basophils, and, interestingly, the envelope glycoprotein of the bovine leukemia virus that induces polyclonal B cell proliferation. Since the genomic structure of each ARAM within c, CD3, Iga, lgp, and the FcsR j3 and y chains is similar (each motif is