Association of signaling proteins with a nonmitogenic heterodimeric complex composed of epidermal growth factor receptor and kinase-inactive p185c-neu.
The functional consequences of heterodimer formation between the epidermal growth factor receptor (EGFr) and the p185c-neu receptor tyrosine kinase include increased mitogenic and transformation potencies. To determine the possible alteration of signal transduction pathways resulting from this heteromeric complex, the capacity of several signaling proteins to associate with the heterodimeric receptors has been assayed. The in vivo interaction with the EGFr/p185c-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 phosphatase SHPTP2, was measured by coimmunoprecipitation. The binding of these signaling proteins to a complex composed of EGFr and a kinase-inactive form of p185 (p185K757M) was not impaired, even though the mitogenic and transformation activity of this complex had been abrogated. In addition, the EGF-induced phosphorylation of GAP, p85, and PLC-gamma 1 did not correlate with the dominant-negative action of p185K757M on EGFr function. Thus, substrate association and phosphorylation do not correlate stringently with the mitogenic and transforming activity of this receptor complex, suggesting additional pathways or mechanisms vital to EGFr/p185c-neu heterodimeric signaling.
Dougall
W C
WC
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Qian
X
X
Miller
M J
MJ
Greene
M I
MI
D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D066246:ErbB Receptors; D011494:Protein Kinases; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases