c-SRC Mediates Neurite Outgrowth through Recruitment of Crk to the Scaffolding Protein Sin/Efs without Altering the Kinetics of ERK Activation

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 modera...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-05, Vol.277 (20), p.17406-17414
Main Authors: Yang, Liang-Tung, Alexandropoulos, Konstantina, Sap, Jan
Format: Article
Language:English
Subjects:
Animals
Enzyme Activation
Epidermal Growth Factor - metabolism
Fluorescent Antibody Technique
Genes, src - physiology
Kinetics
Mitogen-Activated Protein Kinases - metabolism
Neurites - physiology
Neurons - physiology
PC12 Cells
Phosphorylation
Protein Tyrosine Phosphatases - physiology
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-crk
Rats
Receptor-Like Protein Tyrosine Phosphatases, Class 4
Receptors, Cell Surface
Signal Transduction - physiology
src-Family Kinases - metabolism
Tyrosine - metabolism
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Summary: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 α (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 α/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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111902200