PTP-PEST, a scaffold protein tyrosine phosphatase, negatively regulates lymphocyte activation by targeting a unique set of substrates

Abstract

There is increasing interest in elucidating the mechanisms involved in the negative regulation of lymphocyte activation. Herein, we show that the cytosolic protein tyrosine phosphatase PTP‐PEST is expressed abundantly in a wide variety of haemopoietic cell types, including B cells and T cells. In a model B‐cell line, PTP‐PEST was found to be constitutively associated with several signalling molecules, including Shc, paxillin, Csk and Cas. The interaction between Shc and PTP‐PEST was augmented further by antigen receptor stimulation. Overexpression studies, antisense experiments and structure–function analyses provided evidence that PTP‐PEST is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of PTP‐PEST to induce dephosphorylation of Shc, Pyk2, Fak and Cas, and inactivate the Ras pathway. Taken together, these data suggest that PTP‐PEST is a novel and unique component of the inhibitory signalling machinery in lymphocytes.