Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma 2 activation by regulating B cell linker protein-PLC-gamma 2 binding

Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell rec eptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-gamma 2 activation, ther eby leading to increased apoptosis. A possible explanation for the involvem ent of Cbl in PLC-gamma 2 activation was provided by findings that Cbl inte racts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-gamma 2 ty rosine phosphorylation through its binding to the PLC-gamma 2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, die BCR-induced r ecruitment of PLC-gamma 2 to BLNK and the subsequent PLC-gamma 2 tyrosine p hosphorylation were inhibited. Thus, our data suggest that Cbl negatively r egulates the PLC-gamma 2 pathway by inhibiting the association of PLC-gamma 2 with BLNK.