Open Access Review Article Cell Science & Therapy Mulu et al., J Cell Sci Ther 2012, S5 http://dx.doi.org/10.4172/2157-7013.S5-005 J Cell Sci Ther Cytokines ISSN: 2157-7013 JCEST, an open access journal Introduction Contrary to unicellular organisms, cells in multicellular metazoa must divide under strict control. Intercellular communication is crucial in the regulation of cell growth, as well as differentiation and migration, and it oſten occurs indirectly through the release of diffusible growth factors by certain cells that initiate the signal through receptors on target cells. Communication between cells can also be achieved directly, through the gap junctions, i.e., channels running through the membrane which allow the passage of ions and other molecules between the interiors of adjacent cells. Gap junctions consist of the transmembrane proteins, termed connexins, a family of at least 20 members described in mammals. ey are oſten designated with a suffix referring to their molecular weight. Gap junctions are formed by the aggregation of two hemi-channels of six connexons each, contributed by the two neighboring cells. is structure forms an aqueous channel through the two plasma membranes, that permits the passage of small molecules such as ions, nucleotides, aminoacids, short peptides or RNA [1,2] between adjacent cells [3]. Results from a number of labs indicated that an increase in cell proliferation correlates with a reduction in gap junctional, intercellular communication (GJIC). In fact, a number of tumor promotors such as the 12-O-Tetradecanoylphorbol-13-acetate and oncogene products such as the transforming protein of the Rous Sarcoma virus, vSrc [4], the polyoma virus middle Tumor antigen (mT [5,6]), the activated chaperone Hsp90N [7], vRas [8,9] and others have been shown to interrupt junctional communication. Src is an oncogene with a high clinical relevance and one of the best-studied targets for cancer therapy (reviewed in [10]). Src encodes a potent oncoprotein with high tyrosine kinase activity. Among its functions, Src can affect the activity of Cx43 by multiple mechanisms, namely by direct phosphorylation on tyrosine residues, but also by its direct downstream effector pathways, Ras/Raf/Erk and the phosphatidylinositol-3 kinase (PI3k)/Akt that phosphorylate Cx43 on serine residues to disrupt GJIC. In addition, Src may indirectly activate the ser/thr kinase, protein kinase C that can phosphorylate Cx43 and block gap junctions, as well as other kinases such as the cell division cycle-2 (Cdc2) kinase, caseine kinase 1 (Ck1) and protein kinase A [11-17]. Besides activating kinase pathways, Src can also make use of the adaptor protein Cas (Crk associated substrate) that binds Cx43 to suppress gap junctional communication [18], and is a potent activator of the Signal transducer and activator of transcription-3 (Stat3). In this communication we review the prevailing evidence on the role of Src and its effector pathways upon Cx43 and GJIC. Phosphorylation of Cx43 on Tyrosine by the Src kinase A reduction in gap junctional communication of Src-transformed cells was reported for the first time in 1966 [19]. Subsequent cloning of Cx43 enabled a molecular characterisation of the mechanism whereby Src affects Cx43 function, and this led to fundamental studies on Cx43 regulation. A combination of genetic and biochemical evidence indicated that Src can phosphorylate Cx43 directly: At first the SH3 domain of Src binds a proline-rich area between P274 and P284 of Cx43. is brings the Src kinase domain in close proximity to Y265, which is then phosphorylated by Src (Figure 1). e phosphorylated Y265 offers a docking site for the Src, Src-homology-2 (SH2) domain and this enhanced interaction causes the phosphorylation of Y247 of Cx43, which may contribute to GJIC reduction [20-22]. In fact, vSrc co- expression with a Cx43 mutant where tyr247 and tyr265 were replaced by phenylalanine in Cx43 knockout cells, was unable to interrupt communication, indicating that tyr247 and ty265 are important for GJIC suppression by the Src kinase [21]. However, expression of the same Cx43 mutants in Xenopus oocytes can result in the formation of gap junctions, but these gap junctions can be disrupted by Src, indicating that the sites of direct phosphorylation by Src are not required for GJIC *Corresponding author: Leda Raptis, Departments of Microbiology, Immunology and Pathology, Queen’s University, Kingston, Ontario, Canada K7L3N6, Tel: (613) 533 2462 (office/lab)/(613) 533-2450 (secretary); Fax: (613) 533 6796; E-mail: raptisl@queensu.ca Received November 25, 2011; Accepted December 16, 2011; Published December 19, 2011 Citation: Geletu M, Trotman-Grant A, Raptis L (2012) Regulation of Gap Junctional, Intercellular Communication by the Src Oncogene Product and its Effectors. J Cell Sci Ther S5:005. doi:10.4172/2157-7013.S5-005 Copyright: © 2012 Geletu M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Gap junctions are channels that connect the interiors of neighboring cells and are formed by the connexin (Cx) proteins. A reduction in gap junctional, intercellular communication (GJIC) often correlates with increased growth and neoplastic transformation. Cx43 is a widely expressed connexin which can be phosphorylated by the Src oncoprotein tyrosine kinase on tyr247 and 265 and this reduces communication. However, Src activates multiple signalling pathways such as the Ras/Raf/Erk and PLCγ/protein kinase C, which can also phosphorylate Cx43 and interrupt communication. Other Src effectors such as the Crk associated substrate which has an adaptor function, binds Cx43 to suppress gap junctional communication. In sharp contrast, activation of another Src effector, the Signal transducer and activator of transcription-3 (Stat3) is not required for the Src-mediated, GJIC suppression. Interestingly, Stat3 is actually required for the maintenance of gap junctional communication in normal cells with high GJIC. Regulation of Gap Junctional, Intercellular Communication by the Src Oncogene Product and its Effectors Mulu Geletu, Aaron Trotman-Grant and Leda Raptis* Departments of Microbiology, Immunology and Pathology, Queen’s University, Kingston, Ontario, Canada K7L3N6