Desensitization of Ras activation by a feedback disassociation of the SOS-Grb2 complex

Steven B. Waters, Kathleen H. Holt, Susan E. Ross, Li Jyun Syu, Kun Liang Guan, Alan R. Saltiel, Gary A. Koretzky, Jeffrey E. Pessin

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


Activation of Ras by the exchange of bound GDP for GTP is predominantly catalyzed by the guanylnucleotide exchange factor SOS. Receptor tyrosine kinases increase Ras-GTP loading by targeting SOS to the plasma membrane location of Ras through the small adaptor protein Grb2. However, despite the continuous stimulation of receptor tyrosine kinase activity, Ras activation is transient and, in the case of insulin, begins returning to the GDP-bound state within 5 min. We report here that the cascade of serine kinases activated directly by Ras results in a mitogen-activated protein kinase kinase (MEK)-dependent phosphorylation of SOS and subsequent disassociation of the Grb2-SOS complex, thereby interrupting the ability of SOS to catalyze nucleotide exchange on Ras. These data demonstrate a molecular feedback mechanism accounting for the desensitization of Ras-GTP loading following insulin stimulation.

Original languageEnglish (US)
Pages (from-to)20883-20886
Number of pages4
JournalJournal of Biological Chemistry
Issue number36
StatePublished - Sep 8 1995
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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