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Diabetologia. 2012 Oct;55(10):2565-2582. doi: 10.1007/s00125-012-2644-8. Epub 2012 Aug 8.

Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.

Author information

1
Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA.
2
Howard Hughes Medical Institute, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, CLS 16020, 300 Longwood Avenue, Boston, MA, 02115, USA. morris.white@childrens.harvard.edu.

Abstract

The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.

PMID:
22869320
PMCID:
PMC4011499
DOI:
10.1007/s00125-012-2644-8
[Indexed for MEDLINE]
Free PMC Article

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