REGULATION OF CONNEXIN43 FUNCTION BY ACTIVATED TYROSINE PROTEIN-KINASES

Gap junctions are specialized membrane structures that are involved in the normal functioning of numerous mammalian tissues and implicated i n several human disease processes. This minireview focuses on the regu lation of gap junctions through phosphorylation of connexin43 induced by the v-Src or epidermal growth factor receptor tyrosine kinases. The se tyrosine kinases markedly disrupt gap junctional communication in m ammalian cells. Here, we describe work correlating the alteration of c onnexin43 function with the ability of the v-Src tyrosine kinase to ph osphorylate connexin43 directly on two distinct tyrosine sites in mamm alian cells (Y247 and Y265). We also present evidence that proline-ric h regions and phosphotyrosine sites of connexin43 may mediate interact ions with the SH3 and SH2 domains of v-Src. In contrast to v-Src, the activated epidermal growth factor receptor acts indirectly through act ivated MAP kinase which may stimulate phosphorylation of connexin43 ex clusively on serine. This phosphorylation event is complex because MAP kinase phosphorylates three serine sites in connexin43 (S255, S279, a nd S282). These findings suggest novel interactions between connexin43 , the v-Src tyrosine kinase, and activated MAP kinase that set the sta ge for future investigations into the regulation of gap junctions by p rotein phosphorylation.