ASSOCIATION OF SIGNALING PROTEINS WITH A NONMITOGENIC HETERODIMERIC COMPLEX COMPOSED OF EPIDERMAL GROWTH-FACTOR RECEPTOR AND KINASE-INACTIVE P185(C-NEU)

The functional consequences of heterodimer formation between the epide rmal growth factor receptor (EGFr) and the p185(c-neu) receptor tyrosi ne kinase include increased mitogenic and transformation potencies, To determine the possible alteration of signal transduction pathways res ulting from this heteromeric complex, the capacity of several signalin g proteins to associate with the heterodimeric receptors has been assa yed, The in vivo interaction with the EGFr/pl85(c-neu) heterodimer of several signal transduction proteins, including phospholipase C-gamma 1 (PLC-gamma 1), the p85 subunit of phosphotidylinositol 3-kinase, the ras GTPase activating protein, SHC, NCK, p72RAF, and the tyrosine pho sphatase SHPTP2, was measured by coimmunoprecipitation. The binding of these signaling proteins to a complex composed of EGFr and a kinase-i nactive form of p185 (p185K757M) was not impaired, even though the mit ogenic and transformation activity of this complex had been abrogated. In addition, the EGF-induced phosphorylation of GAP, p85, and PLC-gam ma 1 did not correlate with the dominant-negative action of p185K757M on EGFr function, Thus, substrate association and phosphorylation do n ot correlate stringently with the mitogenic and transforming activity of this receptor complex, suggesting additional pathways or mechanisms vital to EGFr/pl85(c-neu) heterodimeric signaling.