title: Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3β to regulate aerobic glycolysis.
abstract: 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.
authors.affiliation: From the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Justine
authors.initials: J
authors.lastname: Landis
authors.affiliation: From the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 leslie.shaw@umassmed.edu.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001692:Biological Transport; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D019344:Lactic Acid; D058539:Phosphatidylinositol 3-Kinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose
keywords: Adaptor Protein; Akt; Breast Cancer; Glut1; Glycogen Synthase Kinase 3 (Gsk-3); Glycolysis; IRS-2; Insulin-like Growth Factor (IGF); PI3K