Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3beta to regulate aerobic glycolysis
Department of Cancer Biology
Medical Subject Headings
Amino Acid Motifs; Animals; Biological Transport; Breast Neoplasms; Down-Regulation; Female; Glucose; Glycogen Synthase Kinase 3; *Glycolysis; Humans; Insulin Receptor Substrate Proteins; Lactic Acid; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinase; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Cells, Cultured
Biochemistry | Cancer Biology
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 3beta (Gsk-3beta). Inhibition of Gsk-3beta 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.
Rights and Permissions
Citation: J Biol Chem. 2014 Jun 27;289(26):18603-13. doi: 10.1074/jbc.M114.564070. Epub 2014 May 8. Link to article on publisher's site
DOI of Published Version
The Journal of biological chemistry
Landis, Justine M. and Shaw, Leslie M., "Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3beta to regulate aerobic glycolysis" (2014). GSBS Student Publications. 1926.