Src is a membrane-bound tyrosine kinase that triggers the transformation of normal cells into cancer cells (1). Src has been implicated a variety of human cancers (2, 3). As expected, metastatic cell growth is significantly reduced by agents that inhibit Src kinase activity (4, 5).Increased anchorage-independent growth and migration distinguish most cancer cells from their nontransformed precursors (6, 7). The Src kinase phosphorylates Cas (Crkassociated substrate) to promote these fundamental hallmarks of tumor cell growth (8 -10). Cas is an important component of the focal adhesion complex signaling network (11) that also includes FAK, Grb2, Shc, and paxillin (12, 13). After phosphorylation by Src, Cas can bind to other proteins including Crk, phosphatidylinositol 3-kinase, Nck, and PLC␥ (14 -16).Src phosphorylates Cas on specific tyrosine residues to promote tumor cell invasion and metastasis. Src transformation of homozygous null Cas knock-out (CasKo) 2 cells does not fully promote their anchorage independence or ability to migrate. These transformed growth characteristics can be conferred to CasKo cells by transfection with wild type Cas (8,10,17,18).Gap junctions form aqueous channels that connect the cytoplasm of adjacent cells. These channels are composed of integral membrane proteins called connexins. Connexins have evolved into a family of at least 20 mammalian members, which are commonly named by their predicted molecular weights (19 -21). Gap junctions allow adjacent cells to share intracellular signals and function in a coordinated fashion (22-24).Connexins play an important role in cell growth control. Experiments have identified Cx43 as a tumor suppressor gene (25-27). In general, gap junctional communication is blocked in transformed cells (28, 29). For example, Cx43 expression is robust in normal glial and mammary cells but repressed in some glioma and mammary tumor cells. Moreover, restoration of Cx43 expression can normalize the growth of glioma and mammary carcinoma cells (27,30,31).Src phosphorylates connexin43 but may require downstream events to block gap junctional communication. Like Cas, Cx43 is a functionally relevant Src substrate. Src phosphorylates Cx43 on critical tyrosine residues, and this event can lead to reduced intercellular communication (32)(33)(34).However, in addition to tyrosine phosphorylation, other factors may be required for Src to block gap junctional communication mediated by Cx43. For example, MAPK acts downstream of Src to phosphorylate Cx43 on serine residues and close gap junction channels (35). Other kinases activated by Src, such as protein kinase C also disrupt junctions formed by Cx43 (36). In addition, other components may be involved since potential SH3 binding domains on Cx43 are required for channel closure in Src-transformed cells (35). Src and Cas both have SH3 domains (37).As described above, Src utilizes Cas to promote tumor cell metastasis (8,10,17,18). Therefore, revealing functional relationships between Cas and Cx43 would aid in understanding ho...
