Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos

L. Buday, P. H. Warne, J. Downward

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Formation of a complex of the nucleotide exchange factor Sos, the SH2 and SH3 containing adaptor protein Grb2/Sem-5 and tyrosine phosphorylated EGF receptor and Shc has been implicated in the activation of Ras by epidermal growth factor (EGF) in fibroblasts: related mechanisms for activation of Ras operate in other cell types. An increase in the apparent molecular weight of Sos has been reported to occur after several minutes of receptor stimulation due to phosphorylation by mitogen-activated protein (MAP) kinases. We report here that treatment of human peripheral blood T lymphoblasts with phorbol esters causes a similar shift in mobility of Sos. This modification of Sos does not alter its ability to bind Grb2, but correlates with strong inhibition of the binding of the Sos/Grb2 complex to tyrosine phosphorylated sequences, either a tyrosine phosphopeptide in cell lysates or p36 in intact cells. This effect, along with the mobility shift of Sos, can be mimicked in vitro by phosphorylation of Sos by the mitogen-activated protein kinase, ERK1. A novel negative feedback mechanism therefore exists whereby activation of MAP kinases through Ras results in the uncoupling of the Sos/Grb2 complex from tyrosine kinase substrates without blocking the interaction of Sos with Grb2.

Original languageEnglish
Pages (from-to)1327-1331
Number of pages5
JournalOncogene
Volume11
Issue number7
Publication statusPublished - 1995

Fingerprint

Mitogen-Activated Protein Kinases
Tyrosine
Down-Regulation
Phosphorylation
Phosphopeptides
Phorbol Esters
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Protein-Tyrosine Kinases
Nucleotides
Fibroblasts
Molecular Weight
Proteins

Keywords

  • MAP kinase
  • Ras
  • Sos
  • T cell

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. / Buday, L.; Warne, P. H.; Downward, J.

In: Oncogene, Vol. 11, No. 7, 1995, p. 1327-1331.

Research output: Contribution to journalArticle

Buday, L, Warne, PH & Downward, J 1995, 'Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos', Oncogene, vol. 11, no. 7, pp. 1327-1331.
Buday, L. ; Warne, P. H. ; Downward, J. / Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. In: Oncogene. 1995 ; Vol. 11, No. 7. pp. 1327-1331.
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