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J. Biol. Chem., Vol. 279, Issue 36, 37662-37669, September 3, 2004

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Tyrosine-phosphorylated SOCS3 Interacts with the Nck and Crk-L Adapter Proteins and Regulates Nck Activation^*

John C. Sitko, Claudia I. Guevara, and Nicholas A. Cacalano

From the Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, Center for Health Sciences, Los Angeles, California 90095

Suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor signal transduction. Although the affect of SOCS proteins on the Jak-STAT pathway has been well characterized, their role in the regulation of other signaling modules is not well understood. In the present study, we demonstrate that SOCS3 physically interacts with the SH2/SH3-containing adapter proteins Nck and Crk-L, which are known to couple activated receptors to multiple downstream signaling pathways and the actin cytoskeleton. Our data show that the SOCS3/Nck and SOCS3/Crk-L interactions depend on tyrosine phosphorylation of SOCS3 Tyr²²¹ within the conserved SOCS box motif and intact SH2 domains of Nck and Crk-L. Furthermore, SOCS3 Tyr²²¹ forms a YXXP motif, which is a consensus binding site for the Nck and Crk-L SH2 domains. Expression of SOCS3 in NIH3T3 cells induces constitutive recruitment of a Nck-GFP fusion protein to the plasma membrane and constitutive tyrosine phosphorylation of endogenous Nck. Our findings suggest that SOCS3 regulates multiple cytokine and growth factor-activated signaling pathways by acting as a recruitment factor for adapter proteins.

Received for publication, April 12, 2004 , and in revised form, May 18, 2004.

^* 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: UCLA Center for Health Sciences, Dept. of Radiation Oncology, Rm. B3-133, Los Angeles, CA 90095. Tel.: 310-267-2803; Fax: 310-206-1260; E-mail: ncacalano{at}mednet.ucla.edu.

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