TOWARDS UNRAVELING THE COMPLEXITY OF T-CELL SIGNAL-TRANSDUCTION

Activation of resting T lymphocytes through the T cell antigen recepto r complex is initiated by critical phosphorylation and dephosphorylati on events that regulate the function and interaction of a number of si gnaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the p hosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate e ach other at multiple sites and, as the result of these interactions, they are induced to phosphorylate other cellular proteins. These phosp horylation events lead to modulation of enzymatic activities and/or se rve as binding sites for other signaling molecules having phosphotyros ine-binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinase s that phosphorylate them. Some of the SH2-domain-containing polypepti des lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effecters, 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 lymphocyt e effector functions, progression through the cell cycle and cell prol iferation.