LACK OF SHPTP1 RESULTS IN SRC-FAMILY KINASE HYPERACTIVATION AND THYMOCYTE HYPERRESPONSIVENESS

Protein tyrosine phosphorylation and dephosphorylation are key regulat ory events in T-cell receptor (TCR) signaling. We investigated the rol e of the tyrosine phosphatase SHPTP1 in TCR signaling by analysis of T CR signal transduction in motheaten (me/me) mice, which lack SHPTP1 ex pression. As revealed by flow cytometric analysis, thymocyte developme nt was normal in me/me mice. However, me/me thymocytes hyperproliferat ed (3- to 5-fold) in response to TCR stimulation, whereas their respon se to interleukin 2 stimulation was unchanged compared with normal thy mocytes. TCR-induced hyperproliferation of me/me thymocytes was reprod uced in purified single-positive thymocytes. However, me/me thymocytes produced increased amounts of interleukin 2 production upon TCR stimu lation. Biochemical analysis revealed that, in response to TCR or TCR/ CD4 stimulation, thymocytes lacking SHPTP1 showed increased tyrosyl ph osphorylation of several cellular substrates, which correlated with in creased activation of the src-family kinases Lck and Fyn. Taken togeth er, our data suggest that SHPTP1 is an important negative regulator of TCR signaling, acting at least in part to inactivate Lck and Fyn.