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dc.contributor.authorLandis, Justine M.
dc.contributor.authorShaw, Leslie M.
dc.date2022-08-11T08:08:55.000
dc.date.accessioned2022-08-23T16:12:28Z
dc.date.available2022-08-23T16:12:28Z
dc.date.issued2014-06-27
dc.date.submitted2015-09-21
dc.identifier.citationJ Biol Chem. 2014 Jun 27;289(26):18603-13. doi: 10.1074/jbc.M114.564070. Epub 2014 May 8. <a href="http://dx.doi.org/10.1074/jbc.M114.564070">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Linking)
dc.identifier.doi10.1074/jbc.M114.564070
dc.identifier.pmid24811175
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33401
dc.description.abstractInsulin 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24811175&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140254/
dc.subjectAmino 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
dc.subjectBiochemistry
dc.subjectCancer Biology
dc.titleInsulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3beta to regulate aerobic glycolysis
dc.typeArticle
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume289
dc.source.issue26
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/1926
dc.identifier.contextkey7622778
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_sp/1926
dc.contributor.departmentDepartment of Cancer Biology
dc.source.pages18603-13
dc.contributor.studentJustine M. Landis


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