Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway

Thangiah Geetha, Paul Langlais, Michael Caruso, Zhengping Yi

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Skeletal muscle insulin resistance is an early abnormality in individuals with metabolic syndrome and type 2 diabetes (T2D). Insulin receptor substrate-1 (IRS1) plays a key role in insulin signaling, the function of which is regulated by both phosphorylation and dephosphorylation of tyrosine and serine/threonine residues. Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. The current study was undertaken to better understand PPP1R12A's role in insulin signaling. Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. These results indicate that PPP1R12A and PP1cd are new members of the insulinstimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cd, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D.

Original languageEnglish (US)
Pages (from-to)437-443
Number of pages7
JournalJournal of Endocrinology
Volume214
Issue number3
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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