Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network; Graduate School of Biomedical Sciences, Cancer Biology Program; Graduate School of Biomedical Sciences, MD/PhD Program; School of Medicine; Senior Scholars Program
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2- but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment.
Akt PKB, apoptosis, breast cancer, cell signaling, insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2), microtubule
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© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/Copyright_Permission.xhtml.
DOI of Published Version
J Biol Chem. 2017 May 12;292(19):7806-7816. doi: 10.1074/jbc.M117.785832. First published 2017 Mar 20.Link to article on publisher's site
The Journal of biological chemistry
Mercado-Matos, Jose; Clark, Jennifer L.; Piper, Andrew J.; Janusis, Jenny; and Shaw, Leslie M., "Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells" (2017). UMass Metabolic Network Publications. 133.