Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling

Keishi Yamauchi, Jeffrey E. Pessin

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Expression of the insulin receptor substrate-1 (IRS1) or Shc cDNA resulted in both increased protein and insulin-stimulated tyrosine phosphorylation of IRS1 and Shc proteins, respectively. Although expression of Shc had no significant effect on insulin-stimulated mitogen-activated protein (MAP) kinase gel shift or c-fos transcriptional activation, expression of IRS1 inhibited these responses. The effect of IRS1 expression on the formation of multisubunit signaling complexes was determined by a series of indirect co- immunoprecipitations. Grb2 immunoprecipitation from IRS1-transfected and insulin-treated cells demonstrated an increased co-immunoprecipitation of Syp and the p85 regulatory subunit of the phosphatidylinositol 3-kinase. Similarly, cell extracts immunoprecipitated with a p85 antibody displayed an increased co-immunoprecipitation of Syp and Grb2. However, expression of IRS1 increased the extent of Grb2 associated with IRS1 with a concomitant reduction in the amount of Grb2 associated with Shc. Furthermore, increased expression of Shc reduced the amount of Grb2 bound to IRS1 with a concomitant increase in Grb2 associated with Shc. Together, these data demonstrate that IRS1 and Shc compete for a limited cellular pool of Grb2, and insulin activation of MAP kinase and c-fos transcription predominantly occur through the Shc-Grb2 signaling pathway.

Original languageEnglish (US)
Pages (from-to)31107-31114
Number of pages8
JournalJournal of Biological Chemistry
Volume269
Issue number49
StatePublished - Dec 9 1994
Externally publishedYes

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Insulin Receptor Substrate Proteins
Insulin
Immunoprecipitation
Mitogen-Activated Protein Kinases
Chemical activation
Phosphatidylinositol 3-Kinase
Phosphorylation
Transcription
Cell Extracts
Transcriptional Activation
Tyrosine
Proteins
Complementary DNA
Gels
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. / Yamauchi, Keishi; Pessin, Jeffrey E.

In: Journal of Biological Chemistry, Vol. 269, No. 49, 09.12.1994, p. 31107-31114.

Research output: Contribution to journalArticle

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