The epidermal growth factor receptor (EGFR) is a key driver in the process of squamous cell carcinoma (SCC) cell mitogenesis. Phospholipase C-gamma 1 (PLC-gamma 1) is a downstream target of EGFR signaling, but the role and necessity of PLC-gamma 1 in EGFR-induced cell mitogenesis remain unclear. In the present study, we report an elevated expression of PLC-gamma 1 in human SCC biopsies relative to adjacent normal epidermis, and in human SCC cell lines compared to normal human keratinocytes. EGFR-induced SCC cell mitogenesis was blocked by small interfering RNA knockdown of PLC-gamma 1. However, inhibition of the catalytic activity of phospholipase C had no effect on EGFR-induced SCC cell mitogenesis. In response to the EGFR ligand epidermal growth factor (EGF), PLC-gamma 1 was translocated not only to the plasma membrane but also to the nucleus. These data suggest that PLC-gamma 1 is required for EGFR-induced SCC cell mitogenesis and the mitogenic function of PLC-gamma 1 is independent of its lipase activity. (C) 2010 Elsevier Inc. All rights reserved.