Two New Substrates in Insulin Signaling, IRS5/DOK4 and IRS6/DOK5
Melendez, Peter A.
Shoelson, Steven E.
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CitationCai, Dongsheng, Sirano Dhe-Paganon, Peter A. Melendez, Jongsoon Lee, and Steven E. Shoelson. 2003. “Two New Substrates in Insulin Signaling, IRS5/DOK4 and IRS6/DOK5.” Journal of Biological Chemistry 278 (28). American Society for Biochemistry & Molecular Biology (ASBMB): 25323–30. doi:10.1074/jbc.m212430200.
AbstractWe have identified two new human genes that encode proteins with tandem pleckstrin homology-phosphotyrosine binding (PH-PTB) domains at their amino termini. Because the other known PH-PTB proteins ( insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. Northern analyses indicate that IRS5/DOK4 is ubiquitously expressed but most abundant in kidney and liver. IRS6/DOK5 expression is highest in skeletal muscle. Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cgamma Src homology 2 domains, and activates MAPK in cells. IRS6/DOK5 neither associates with these Src homology 2 domains nor activates MAPK. IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action.
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