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J Biol Chem. 2014 Jun 27;289(26):18603-13. doi: 10.1074/jbc.M114.564070. Epub 2014 May 8.

Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis.

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  • 1From the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
  • 2From the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 leslie.shaw@umassmed.edu.


Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. To determine the contribution of Irs-2-dependent PI3K signaling to this selective regulation, we generated an Irs-2 mutant deficient in the recruitment of PI3K. We identified four tyrosine residues (Tyr-649, Tyr-671, Tyr-734, and Tyr-814) that are essential for the association of PI3K with Irs-2 and demonstrate that combined mutation of these tyrosines inhibits glucose uptake and lactate production, two measures of aerobic glycolysis. Irs-2-dependent activation of PI3K regulates the phosphorylation of specific Akt substrates, most notably glycogen synthase kinase 3β (Gsk-3β). Inhibition of Gsk-3β by Irs-2-dependent PI3K signaling promotes glucose uptake and aerobic glycolysis. The regulation of unique subsets of Akt substrates by Irs-1 and Irs-2 may explain their non-redundant roles in mammary tumor biology. Taken together, our study reveals a novel mechanism by which Irs-2 signaling preferentially regulates tumor cell metabolism and adds to our understanding of how this adaptor protein contributes to breast cancer progression.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Adaptor Protein; Akt; Breast Cancer; Glut1; Glycogen Synthase Kinase 3 (Gsk-3); Glycolysis; IRS-2; Insulin-like Growth Factor (IGF); PI3K

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