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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
c-SRC Mediates Neurite Outgrowth through Recruitment of Crk
to the Scaffolding Protein Sin/Efs without Altering the Kinetics of
ERK Activation*,
Liang-Tung
Yang ,
Konstantina
Alexandropoulos§, and
Jan
Sap ¶
From the 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 (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 /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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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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