We have examined the distribution of phospholipase C-gamma 1 (PLC-gamma 1) between membrane and cytosolic fractions in several cell lines. In MDA-468 cells, which are derived from a human breast tumor, greater than one-half of the total PLC-gamma 1 is associated with the membrane fraction of the cell. Unlike the situation in A-431 cells [G. Todderud, M. I. Wahl, S. G. Ree, and G. Carpenter, Science, 248: 296-298, 1990], epidermal growth factor (EGF) stimulation of MDA-468 cells does not result in significantly increased PLC-gamma 1 association with membranes. Immunoblot analysis reveals low levels of phosphotyrosine in PLC-gamma 1 and EGF receptors in unstimulated MDA-468 cells and greatly increased phosphotyrosine levels in these proteins as a result of EGF stimulation of the cells. We conclude that autocrine activation of EGF receptors is not responsible for the elevated association of PLC-gamma 1 with membranes in these cells.