Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Cancer Biology | Cell Biology | Enzymes and Coenzymes | Hormones, Hormone Substitutes, and Hormone Antagonists | Molecular Biology
Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion, and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor (IR) activation and the recruitment and activation of phosphatidylinositol 3-kinase (PI3K), functions shared with IRS1. In addition, a 174-amino-acid region in the IRS2 C-terminal tail, which is not conserved in IRS1, is also required for IRS2-mediated invasion. Importantly, this "invasion (INV) region" is sufficient to confer invasion-promoting ability when swapped into IRS1. However, the INV region is not required for the IRS2-dependent regulation of glucose uptake. Bone morphogenetic protein 2-inducible kinase (BMP2K) binds to the INV region and contributes to IRS2-dependent invasion. Taken together, our data advance the mechanistic understanding of how IRS2 regulates invasion and reveal that IRS2 functions important for cancer can be independently targeted without interfering with the metabolic activities of this adaptor protein.
IGF-1R, IRS2, PI3K, breast cancer, invasion
Rights and Permissions
Copyright © 2018, American Society for Microbiology. Publisher PDF posted after 6 months as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
DOI of Published Version
Mol Cell Biol. 2018 Jun 28;38(14). pii: e00590-17. doi: 10.1128/MCB.00590-17. Print 2018 Jul 15. Link to article on publisher's site
Molecular and cellular biology
Mercado-Matos, Jose; Janusis, Jenny; Zhu, Sha; Chen, Samuel S.; and Shaw, Leslie M., "Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2" (2018). University of Massachusetts Medical School Faculty Publications. 1577.
Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Cancer Biology Commons, Cell Biology Commons, Enzymes and Coenzymes Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, Molecular Biology Commons