Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways

Liangyou Rui, Vincent Aguirre, Jason K. Kim, Gerald I. Shulman, Anna Lee, Anne Corbould, Andrea Dunaif, Morris F. White*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

448 Scopus citations

Abstract

Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. To monitor phosphorylation of Ser307 in various cell and tissue backgrounds, we prepared a phosphospecific polyclonal antibody designated αpSer307. This antibody revealed that TNF-α, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-α-stimulated phosphorylation was inhibited by PD98059. Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response.

Original languageEnglish (US)
Pages (from-to)181-189
Number of pages9
JournalJournal of Clinical Investigation
Volume107
Issue number2
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Medicine(all)

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