UMMS Affiliation

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

Date

5-12-2017

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

Abstract

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.

Rights and Permissions

© 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. Citation: 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

Comments

First author Jose Mercado-Matos is a doctoral student in the Cancer Biology and MD/PhD programs in Graduate School of Biomedical Sciences at UMass Medical School.

Co-author Andrew J. Piper participated in this study as a medical student in the Senior Scholars research program at the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

Keywords

Akt PKB, apoptosis, breast cancer, cell signaling, insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2), microtubule

PubMed ID

28320862

Available for download on Saturday, May 12, 2018

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