Insulin receptor substrate (IRS)-2 is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells

Takehide Ogihara, Bo Chul Shin, Motonobu Anai, Hideki Katagiri, Kouichi Inukai, Makoto Funaki, Yasushi Fukushima, Hisamitsu Ishihara, Kuniaki Takata, Masatoshi Kikuchi, Yoshio Yazaki, Yoshitomo Oka, Tomoichiro Asano

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75 Citations (Scopus)

Abstract

Insulin receptor substrate (irs)-2 is structurally and functionally similar to Irs-1. Indeed, stimulation with insulin or insulin-like growth factor I led to the rapid tyrosine phosphorylation of both Irs-1 and Irs-2, which in turn activated phosphatidylinositol (pi) 3-kinase in L6 cells and rat skeletal muscle. However, Irs-2 was rapidly dephosphorylated (3-10 min after the addition of insulin/insulin-like growth factor I), whereas Irs-1 phosphorylation continued for at least 60 min. The time courses of the Pi 3- kinase activity associated with Irs-1 and Irs-2 paralleled the tyrosine phosphorylation of these proteins. Preincubation with sodium orthovanadate, an inhibitor of protein tyrosine phosphatase, blocked the rapid dephosphorylation of Irs-2, suggesting the involvement of tyrosine phosphatase. The activation of Pi 3-kinase apparently plays an important role in the rapid dephosphorylation of Irs-2, as Irs-2 dephosphorylation was inhibited markedly by suppressing Pi 3-kinase activity with wortmannin or overexpression of the dominant negative p85 subunit of pi 3-kinase, which cannot bind the p110 catalytic subunit. In addition, platelet-derived growth factor stimulation prior to insulin stimulation decreased Irs-associated Pi 3-kinase and significantly inhibited the dephosphorylation of Irs-2. Taken together, these observations suggest that Irs-2 plays a unique role in mediating the signals from the insulin receptor to downstream molecules and that this effect is more transient than that of Irs-1. Tyrosine phosphatase and Irs-associated Pi 3-kinase activity thus contribute to the rapid dephosphorylation of Ir-2.

Original languageEnglish
Pages (from-to)12868-12873
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number19
DOIs
Publication statusPublished - 1997 May 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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