Focal adhesion kinase promotes phospholipase C-gamma l activity

The nonreceptor tyrosine kinase FAK ("focal adhesion kinase") is a key medi ator of integrin signaling events controlling cellular responses to the ext racellular matrix, including spreading, migration, proliferation, and survi val. Integrin-ligand interactions stimulate FAK tyrosine phosphorylation an d activation of FAK signaling functions. Here evidence is presented that th e FAK autophosphorylation site Tyr-397 mediates a direct interaction with t he C-terminal Src homology 2 domain of phospholipase C (PLC)-gamma 1 and th at this is required for both adhesion-dependent association of the two mole cules and increased inositol phosphate production in mouse embryo fibroblas ts. Overexpression of FAR and PLC-gamma 1 in COS-7 cells increases PLC-gamm a 1 enzymatic activity and tyrosine phosphorylation, also dependent on FAK Tyr-397. However, FAK appears incapable of directly phosphorylating PLC-gam ma 1. These observations suggest a role for FAK in recruiting PLC-gamma 1 t o the plasma membrane at sites of cell-matrix adhesion and there promoting its enzymatic activity, possibly by releasing the repression caused by intr amolecular interactions of the PLC-gamma 1 Src homology domains and/or by p ositioning it for phosphorylation by associated Src-family kinases. These f indings expand the known signaling functions of FAR and provide mechanistic insight into integrin-stimulation of PLC-gamma 1.