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¹ Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
² Department of Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8553, Japan
³ Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima 734-8553, Japan
⁴ Department of Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan
⁵ Growth Factor Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
⁶ Department of Allergy and Rheumatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
⁷ Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

p130Cas (Cas, Crk-associated substrate) is an adaptor molecule composed of a Src homology 3 (SH3) domain, a substrate domain (SD) and a Src binding domain (SBD). The SH3 domain of Cas associates with focal adhesion kinase (FAK), but its role in cellular function has not fully been understood. To address this issue, we established and analyzed primary fibroblasts derived from mice expressing a truncated Cas lacking exon 2, which encodes the SH3 domain (Cas exon 2). In comparison to wild-type cells, Cas exon 2^/ cells showed reduced motility, which could be due to impaired tyrosine-phosphorylation of FAK and Cas, reduced FAK/Cas/Src/CrkII binding, and also impaired localization of Cas exon 2 to focal adhesions on fibronectin. In addition, to analyze downstream signaling pathways regulated by Cas exon 2, we performed microarray analyses. Interestingly, we found that a deficiency of Cas exon 2 up-regulated expression of CXC Chemokine Receptor-4 and CC Chemokine Receptor-5, which may be regulated by IB phosphorylation. These results indicate that the SH3-encoding exon of Cas participates in cell motility, tyrosine-phosphorylation of FAK and Cas, FAK/Cas/Src/CrkII complex formation, recruitment of Cas to focal adhesions and regulation of cell motility-associated gene expression in primary fibroblasts.

^* Correspondence: E-mail: hhonda{at}hiroshima-u.ac.jp