Phospholipase C-gamma 1 (PLC-gamma 1), a tyrosine kinase substrate, has been implicated in the pathway for the epidermal growth factor receptor (EGFR)-induced cell migration. However, the underlying mechanism by which PLC-gamma 1 mediates EGFR-induced cell migration remains elusive. In the present study, we sought to determine whether the lipase activity of PLC-gamma 1 is required for EGFR-induced cell migration. We found that overexpression of PLC-gamma 1 in squamous cell carcinoma SCC4 cells markedly enhanced EGF-induced PLC-gamma 1 activation, intracellular calcium rise, and cell migration. This enhancement was abolished by mutational inactivation of the catalytic domain of PLC-gamma 1. Inhibition of the downstream signaling processes mediated by the activity of phospholipase C (PLC) using IP3 receptor inhibitor or intracellular calcium chelator blocked EGF-induced cell migration. These data indicate that EGF-induced cell migration is mediated by the lipase domain of PLC-gamma 1 and the subsequent IP3 generation and intracellular calcium mobilization. (C) 2010 Elsevier Inc. All rights reserved.