Src homology domains in phospholipase C-gamma1 mediate its anti-apoptotic action through regulating the enzymatic activity

Phospholipase-gamma1 (PLC-gamma1) prevents programmed cell death, for which the enzymatic activity has been implicated. However, the biological function of Src homology (SH) domains of PLC-gamma1 in promoting cell survival remains elusive. Here, we showed that deletion of the N-SH2 domain or both N-SH2 and C-SH2 domains, but not the SH3 domain, abolished the anti-apoptotic activity of PLC-gamma1. Surprisingly, removal of the whole SH domain inhibited apoptosis. The lipase-inactive PLC-gamma1 mutant (LIM) failed to suppress apoptosis. Moreover, the phospholipase activity in SH3- or whole SH domain-deleted cells was comparable to that of wild-type cells. By contrast, the enzymatic activity was substantially ablated in SH2 domain-deleted or LIM cells. A pharmacological inhibitor of PLC-gamma1 robustly diminished the anti-apoptotic action in wild-type, SH3- or whole SH domain-deleted cells, whereas pretreatment of SH2 domain-deleted or LIM cells with agents activating PKC and calcium mobilization markedly promoted cell survival. These results indicate that SH domains in PLC-gamma1 might mediate its anti-apoptotic action by regulating the enzymatic activity.