The signaling pathway coupling epidermal growth factor receptors to activation of p21ras.
Epidermal growth factor (EGF) treatment causes autophosphorylation of the epidermal growth factor receptor (EGFR) leading to increased guanine nucleotide exchange factor (GEF; Sos) activity and enhanced formation of p21ras-GTP. The connection of the EGFR to p21ras activation can occur through binding of Grb2.Sos complexes to the EGFR or through the adaptor protein Shc via EGFR.Shc.Grb2.Sos multimeric complexes. Therefore, we investigated the importance of Shc in coupling the EGFR to activation of ras GEF (Sos). EGF treatment led to rapid tyrosine phosphorylation of Shc. Although phosphorylated EGFR can bind to both Shc and Grb2, the predominant linkage was observed between EGFR and Shc. Similarly, more Grb2 was associated with Shc than with EGFR after EGF stimulation. Immunoprecipitation of Shc from EGF-stimulated cells removed almost all EGFR-associated Grb2. Furthermore, immunodepletion of Shc proteins from membrane fractions of EGF-stimulated cells removed 93% of the ras GEF activity, whereas, precipitation of EGFR had only a small effect on ras GEF activity. These data indicate that coupling to Shc provides the major pathway linking activated EGFRs to Grb2.Sos and stimulation of the p21ras pathway.
Sasaoka
T
T
Department of Medicine, University of California, San Diego, La Jolla 92093.
Langlois
W J
WJ
Leitner
J W
JW
Draznin
B
B
Olefsky
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D011506:Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras)