Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase

The protein-tyrosine phosphatase SHP-1 has been shown to be a negative regu lator of multiple signaling pathways in hematopoietic cells. In this study, we demonstrate that SHP-1 dephosphorylates the lymphoid-specific Src famil y kinase Lck at Tyr-394 when both are transiently co-expressed in nonlympho id cells. We also demonstrate that a GST-SHP-1 fusion protein specifically dephosphorylates Lck at Tyr-394 in vitro. Because phosphorylation of Tyr-39 4 activates Lck, the fact that SHP-1 specifically dephosphorylates this sit e suggests that SHP-1 is a negative regulator of Lck. The failure of SHP-1 to inactivate Lck may contribute to some of the lymphoid abnormalities obse rved in motheaten mice.