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Vol. 17, Issue 7, 3187-3196, July 2006
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*Laboratory for Molecular Neurogenesis, Riken Brain Science Institute, Wako, Saitama 351-0198; and Growth Factor Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
Submitted December 13, 2005;
Revised April 25, 2006;
Accepted May 1, 2006
Monitoring Editor: Richard Assoian
Crk-associated substrate (Cas) is a tyrosine-phosphorylated docking protein that is indispensable for the regulation of the actin cytoskeletal organization and cell migration in fibroblasts. The function of Cas in neurons, however, is poorly understood. Here we report that Cas is dominantly enriched in the brain, especially the cerebellum, of postnatal mice. During cerebellar development, Cas is highly tyrosine phosphorylated and is concentrated in the neurites and growth cones of granule cells. Cas coimmunoprecipitates with Src family protein tyrosine kinases, Crk, and cell adhesion molecules and colocalizes with these proteins in granule cells. The axon extension of granule cells is inhibited by either RNA interference knockdown of Cas or overexpression of the Cas mutant lacking the YDxP motifs, which are tyrosine phosphorylated and thereby interact with Crk. These findings demonstrate that Cas acts as a key scaffold that links the proteins associated with tyrosine phosphorylation signaling pathways to the granule cell axon elongation.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Teiichi Furuichi ( tfuruichi{at}brain.riken.jp)
Abbreviations used: Cas, Crk associated substrate; YP-Cas, tyrosine phosphorylated Cas; SD, substrate domain; SBD, Src binding domain; PTK, protein tyrosine kinases; CAM, cell adhesion molecules; NCAM, neuronal cell adhesion molecule; EGL, external granule cell layer; ML, molecular layer; IGL, internal granule cell layer; PL, Purkinje cell layer; WM, white matter; EGFP, enhanced green fluorescent protein; GCP, growth cone particle
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