Phospholipase Cγ2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase

Integrin engagement induces a cascade of signaling pathways that include tyrosine phosphorylation of numerous proteins that lead to modulation of the actin cytoskeleton. Src is a major intracellular mediator of integrin-dependent functions, but the mechanism(s) by which Src is regulated in response to integrin signals is not fully understood. Here, we demonstrate an important role for phospholipase C gamma 2 (PLC gamma 2) in Src activation in the osteoclast. Through analysis of primary cells from PLC gamma 2(-/-) mice, PLC gamma 2 was found to be an important regulator of alpha(v)beta(3) integrin-mediated bone osteoclast cell adhesion, migration, and bone resorption. Adhesion-induced PYK2 and Src phosphoryllation is decreased in the absence of PLC gamma 2, and the interaction of Src with beta(3) integrin and PYK2 is dramatically reduced. Importantly, PLC gamma 2 was found to be required for proper localization of Src to the sealing actin ring, and this function required both its catalytic activity and adapter domains. Based on these results, we propose that PLC gamma 2 influences Src activation by mediating the localization of Src to the integrin complex and thereby regulating integrin-mediated functions in the osteoclast.