GSBS Student Publications


Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3beta to regulate aerobic glycolysis

Student Author(s)

Justine M. Landis

GSBS Program

Cancer Biology

UMMS Affiliation

Department of Cancer Biology



Document Type


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


Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID