Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway

Ami Aronheim*, David Engelberg, Nanxin Li, Nadia Al-Alawi, Joseph Schlessinger, Michael Karin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

446 Scopus citations

Abstract

Activation of growth factor receptors results in tyrosine autophosphorylation and recruitment of SH2 domain-containing effectors, including Grb2. Grb2 recruitment mediates activation of the Ras nucleotide exchanger Sos by an unknown mechanism. To examine the role of membrane recruitment, we prepared Sos derivatives containing either myristoylation or farnesylation signals. This resulted in plasma membrane targeting of Sos and stimulation of the Ras signaling pathway, including ERK and AP-1 activities leading to oncogenic transformation. Sos derivatives with nonfunctional myristoylation or farnesylation sequences were inactive. Farnesylation of Sos also activated Ras signaling in yeast. In both mammalian cells and yeast, membrane-targeted Sos derivatives lacking the C-terminal region were considerably more active. Therefore, targeting of Sos to the plasma membrane in the vicinity of Ras appears to be the primary mechanism leading to activation of the Ras pathway. A secondary mechanism could involve relief of the inhibitory effect of the Sos C-terminal region.

Original languageAmerican English
Pages (from-to)949-961
Number of pages13
JournalCell
Volume78
Issue number6
DOIs
StatePublished - 23 Sep 1994
Externally publishedYes

Bibliographical note

Funding Information:
Correspondence should be addressed to M. K. We thank T. Deng, A. Minden, A. Helmberg, B. Wasylyk, R. A. Weinberg, A. Levitzki. M. Segal, C. Marshall, and M. D. Walker for plasmids and yeast strains. We acknowledge discussions with the students attending the signal transduction class taught by M. K.. which led to this work. N. A. A. acknowledges the support of J. Feramisco. A. A. and D. E. were supported by postdoctoral fellowships from the Human Frontiers Science Program Organization. Work in the M. K. lab was supported by grants from the National Institutes of Health, American Cancer Society, and the Department of Energy. Work in the J. S. lab was supported by a grant from Sugen Inc.

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