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J. Biol. Chem., Vol. 280, Issue 7, 6036-6046, February 18, 2005

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Srcasm Modulates EGF and Src-kinase Signaling in Keratinocytes^*

Weijie Li, Christine Marshall, Lijuan Mei, Leonard Dzubow, Chrysalene Schmults, Michael Dans, and John Seykora

From the Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104

The Src-activating and signaling molecule (Srcasm) is a recently described activator and substrate of Src-family tyrosine kinases (SFKs). When phosphorylated at specific tyrosines, Srcasm associates with Grb2 and p85, the regulatory subunit of phosphoinositide 3-kinase; however, little is known about the role of Srcasm in cellular signaling. Data presented here demonstrate that epidermal growth factor (EGF) receptor ligands promote the tyrosine phosphorylation of endogenous and adenovirally transduced Srcasm in keratinocytes, and that increased levels of Srcasm activate endogenous SFKs, with a preference for Fyn and Src. In addition, Srcasm potentiates EGF-dependent signals transmitted by SFKs in keratinocytes. Tyrosine phosphorylation of Srcasm is dependent on growth factors and the activity of EGFR and SFKs. Increased Srcasm expression enhances p44/42 mitogen-activated protein kinase activity and Elk-1-dependent transcriptional events. Elevated Srcasm levels inhibit keratinocyte proliferation while promoting specific aspects of keratinocyte differentiation. Lastly, Srcasm levels are decreased in human cutaneous neoplasia. Collectively, these data demonstrate that Srcasm plays a role in linking EGF receptor- and SFK-dependent signaling to differentiation in keratinocytes.

Received for publication, June 11, 2004 , and in revised form, October 12, 2004.

^* This work was supported by the University of Pennsylvania and the Department of Dermatology, University of Pennsylvania Medical School, by National Institutes of Health Grants KO8-AR47597 and NCI P01-CA098101, and by a Career Development Award from the Dermatology Foundation (to J. 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: Dept. of Dermatology, University of Pennsylvania Medical School, 211a Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0170; Fax: 215-573-2033; E-mail: john.seykora{at}uphs.upenn.edu.

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