Georg Zenner, Jan Dirk zur Hausen, Paul Burn and Tomas Mustelin Summary zyxwvutsrqp Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of these interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine-binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2-domain-containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine-specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle Accepted 25 August 1995 and cell proliferation. Introduction The main function of T lymphocytes is to recognize and respond to foreign antigenic peptides bound to major histo- compatibility complex (MHC)t molecules on antigen pre- senting cells. Depending on the predisposition of the responding T cells, the triggering of the T cell receptor (TCR) leads either to cytotoxicity against antigen-express- ing target cells (in the case of a cytotoxic T cell) or to the recruitment and activation of other cells of the immune sys- tem through the production and secretion of bioactive lym- phokines (in the case of a helper T cell). The helper T cells can be subdivided into T h l and Th2 subclasses, which secrete distinct sets of lymphokines having quite different effects on the immune response. If appropriate secondary TAbbreviations: bcr. break-cluster region; GAP, GTPase-activating protein; ITAM, immunoreceptor tyrosine-based activation motif; MHC, major histocompatibility complex: PLC, phospholipaseC; P13K, phosphatidylinositol 3-kinase; PTK, protein tyrosine kinase; Pro, proline-rich domain; PTB, phosphotyrosine-binding domain: PTPase, phosphotyrosine phosphatase; SH1,2, 3, 4, src homology 1, 2, 3, 4 domain; TCR, T cell antigen receptor. signals are present, the triggering of the TCR also results in progression through the cell cycle and clonal expansion. On the biochemical level, triggering of the TCR is known to cause a large number of changes in the T cell, including early events at the plasma membrane, and through cyto- plasmic and eventually nuclear reactions, culminating in transcription of a number of genes (Fig. 1). The initial events triggered by the TCR and its co-receptors are a natural start- ing point for studies of this manifestly complex process. A few years ago, the importance of tyrosine phosphorylation in these events was recognized, and much work has been devoted to the identification of the protein tyrosine kinases (PTKs) that are involved in T cell activation, and the mech- anisms by which these enzymes are regulated(’). More recent studies are aimed at elucidating the involvement of phosphotyrosine phosphatases (PTPases) in the initial sig- naling events. In addition, the identification of substrates of the kinases and PTPases and their involvement in the com- plex signaling cascades that transduce the signals arriving