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J. Biol. Chem., Vol. 278, Issue 28, 25323-25330, July 11, 2003

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Two New Substrates in Insulin Signaling, IRS5/DOK4 and IRS6/DOK5^*

Dongsheng Cai, Sirano Dhe-Paganon, Peter A. Melendez, Jongsoon Lee and Steven E. Shoelson 

From the Joslin Diabetes Center and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

We 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 C 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.

Received for publication, December 6, 2002 , and in revised form, May 1, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AK001350 and AF466368.

^* This work was supported by National Institutes of Health Grant R01 DK43123 (to S. E. S.), Joslin DERC Grant DK36836, a Mary K. Iacocca Fellowship (to S. D.), NRSA Grant F32 DK61187 from the National Institutes of Health (to P. A. M.), and the Helen and Morton Adler Chair (to S. E. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Tel.: 617-732-2528; Fax: 617-735-1970; E-mail: Steven.Shoelson{at}joslin.harvard.edu.

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