SRC KINASE-ACTIVITY IS REGULATED BY THE SHP-1 PROTEIN-TYROSINE-PHOSPHATASE

Activation of the cellular Src tyrosine kinase depends upon dephosphor ylation of the carboxyl-terminal inhibitory tyrosine phosphorylation s ite. Herein we show that Src isolated from human platelets and Jurkat T cells is preferentially dephosphorylated at its inhibitory phosphoty rosine site by the SHP-1 tyrosine phosphatase. The data also revealed association of Src with SHP-1 in both platelets and lymphocytes and th e capacity of Src to phosphorylate SHP-1 and interact with the SHP-1 N H2-terminal SH2 domain in vitro. Analysis of Src activity in thymocyte s from SHP-1-deficient motheaten and viable motheaten mice revealed th is kinase activity to be substantially lower than that detected in wil d-type thymocytes, but to be enhanced by in vitro exposure to SHP-1. S imilarly, immunoblotting analysis of thymocyte Src expression before a nd after selective depletion of active Src protein indicated that the proportion of active relative to inactive Src protein is markedly redu ced in motheaten compared with wild-type cells. These observations, to gether with the finding of reduced Src activity in HEY cells expressin g a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation.