Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2
Document Type
Journal ArticlePublication Date
2018-06-28Keywords
IGF-1RIRS2
PI3K
breast cancer
invasion
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
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1128/MCB.00590-17Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29351PubMed ID
29685905Related Resources
Rights
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.ae974a485f413a2113503eed53cd6c53
10.1128/MCB.00590-17