NEGATIVE REGULATION OF T-CELL ANTIGEN RECEPTOR SIGNAL-TRANSDUCTION BYHEMATOPOIETIC TYROSINE PHOSPHATASE (HEPTP)

The hematopoietic tyrosine phosphatase (HePTP) is predominantly expres sed in thymocytes and T lymphocytes and at lower levels in other hemat opoietic cells. Expression of the gene is enhanced by the T cell growt h factor interleukin-2, suggesting a role for HePTP in T cell prolifer ation or differentiation. We report that HePTP blocks T cell antigen r eceptor (TCR)-induced transcriptional activation of a reporter gene dr ivels by a nuclear factor of activated T cells(NFAT)/AP-1 element take n from the interleukin-2 genre promotes. This effect was specific to H ePTP and was abolished by a mutation (C270S) that impaired its phospha tase activity. Co-expression of HePTP also reduced TCR-induced activat ion of the mitogen-activated protein kinase Erk2 and the TCR-induced a ppearance of phosphorylated Erk. In contrast, HePTP did not affect the activation of the N-terminal e-Jun kinase, Jnk. Together these findin gs suggest that HePTP plays an active negative role in TCR signaling b y dephosphorylating one or several signaling molecules between the rec eptor and the mitogen-activated protein kinase pathway.