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J. Biol. Chem., Vol. 282, Issue 26, 18914-18921, June 29, 2007

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Src Utilizes Cas to Block Gap Junctional Communication Mediated by Connexin43^*

Yongquan Shen, P. Raaj Khusial, Xun Li, Hitoshi Ichikawa, Alonso P. Moreno^¶, and Gary S. Goldberg¹

From the Department of Molecular Biology, Science Center, University of Medicine and Dentistry, Stratford, New Jersey 08084, the Cancer Transcriptome Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan, and the ^¶Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112

The Src tyrosine kinase phosphorylates Cas (Crk-associated substrate) to confer anchorage independence and invasive growth potential to transformed cells. Gap junctional communication is often lower between aggressive tumor cells compared with normal or benign precursors. The gap junction protein connexin43 (Cx43) is a tumor suppressor that can inhibit tumor cell growth. Src can phosphorylate Cx43 to block gap junctional communication between transformed cells. However, mechanisms by which this event actually closes intercellular channels have not been clearly defined. Here, we report that Src and Cas associate with each other at intercellular junctions. In addition, Cas is required for Src to reduce dye transfer and electrical coupling between cells expressing Cx43. Thus, Src utilizes Cas to inhibit gap junctional communication mediated by Cx43. This finding introduces a novel role of the Cas focal adhesion linker protein in the gap junction complex. This observation may help explain how gap junctional communication can be suppressed between malignant and metastatic tumor cells.

Received for publication, September 20, 2006 , and in revised form, May 2, 2007.

^* This work was supported by National Institutes of Health Grants CA88805 and EY014479 (to G. S. G.) and HL63969 (to A. P. M.), by the Nora Eccles Treadwell Foundation (to A. P. M.), and by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to H. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology, Science Center, 2 Medical Center Dr., University of Medicine and Dentistry, Stratford, NJ 08084. Tel.: 856-566-6718; Fax: 856-566-6291; E-mail: garygoldberg{at}comcast.net.

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