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 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.