Epidermal growth factor receptor targeting prevents uncoupling of the Grb2-SOS complex

Kathleen H. Holt, Steven B. Waters, Shuichi Okada, Keishi Yamauchi, Stuart J. Decker, Alan R. Saltiel, David G. Motto, Gary A. Koretzky, Jeffrey E. Pessin

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Insulin stimulates the Ras/Raf/MEK/ERK pathway leading to feedback phosphorylation of the Ras guanyl-nucleotide exchange protein SOS and dissociation of Grb2 from SOS. Even though epidermal growth factor (EGF) also stimulates ERK activity and phosphorylation of SOS similar to insulin, EGF induces a dissociation of the Grb2-SOS complex from Shc. To determine the molecular basis for this difference, we examined the signaling properties of a mutant EGF receptor lacking the five major autophosphorylation sites. Although EGF stimulation of the mutant EGF receptor activates ERK and phosphorylation of both Shc and SOS, it fails to directly associate with either Shc or Grb2. However, under these conditions EGF induces a dissociation of the Grb2-SOS complex suggesting a role for receptor and/or plasma membrane targeting in the stabilization of Grb2-SOS interaction. Consistent with this hypothesis, expression of an SH2 domain Grb2 mutant which is unable to mediate plasma membrane targeting of the Grb2-SOS complex results in both insulin- and EGF-stimulated uncoupling of Grb2 from SOS. Furthermore, a plasma membrane-bound Grb2 fusion protein remains constitutively associated with SOS. Together, these data demonstrate that EGF stimulation prevents the feedback uncoupling of Grb2 from SOS by inducing a persistent plasma membrane receptor targeting of the Grb2-SOS complex.

Original languageEnglish (US)
Pages (from-to)8300-8306
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number14
DOIs
StatePublished - Apr 5 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Holt, K. H., Waters, S. B., Okada, S., Yamauchi, K., Decker, S. J., Saltiel, A. R., Motto, D. G., Koretzky, G. A., & Pessin, J. E. (1996). Epidermal growth factor receptor targeting prevents uncoupling of the Grb2-SOS complex. Journal of Biological Chemistry, 271(14), 8300-8306. https://doi.org/10.1074/jbc.271.14.8300