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Originally published In Press as doi:10.1074/jbc.M111902200 on February 26, 2002

J. Biol. Chem., Vol. 277, Issue 20, 17406-17414, May 17, 2002
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c-SRC Mediates Neurite Outgrowth through Recruitment of Crk to the Scaffolding Protein Sin/Efs without Altering the Kinetics of ERK Activation*,

Liang-Tung YangDagger , Konstantina Alexandropoulos§, and Jan SapDagger

From the Dagger  Department of Pharmacology, New York University School of Medicine, New York, New York 10016 and § Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

SRC family kinases have been consistently and recurrently implicated in neurite extension events, yet the mechanism underlying their neuritogenic role has remained elusive. We report that epidermal growth factor (EGF) can be converted from a non-neuritogenic into a neuritogenic factor through moderate activation of endogenous SRC by receptor-protein-tyrosine phosphatase alpha  (a physiological SRC activator). We show that such a qualitative change in the response to EGF is not accompanied by changes in the extent or kinetics of ERK induction in response to this factor. Instead, the pathway involved relies on increased tyrosine phosphorylation of, and recruitment of Crk to, the SRC substrate Sin/Efs. The latter is a scaffolding protein structurally similar to the SRC substrate Cas, tyrosine phosphorylation of which is critical for migration in fibroblasts and epithelial cells. Expression of a dominant negative version of Sin interfered with receptor-protein-tyrosine phosphatase alpha /EGF- as well as fibroblast growth factor-induced neurite outgrowth. These observations uncouple neuritogenic signaling in PC12 cells from sustained activation of ERK kinases and for the first time identify an effector of SRC function in neurite extension.

* This work was supported by National Institutes of Health Grant CA68365, a grant from the American Heart Association (New York City affiliate), and a Hirschl career scientist award.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

To whom correspondence should be addressed.: Dept. of Pharmacology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-7120; Fax: 212-263-7133; E-mail: jan.sap@med.nyu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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