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Interaction of c-Src with Gap Junction Protein Connexin-43

B. Giepmans,T. Hengeveld,F. Postma,W. Moolenaar

Published 2001 in Journal of Biological Chemistry

ABSTRACT

Cell-cell communication via connexin-43 (Cx43)-based gap junctions is transiently inhibited by certain mitogens, but the underlying regulatory mechanisms are incompletely understood. Our previous studies have implicated the c-Src tyrosine kinase in mediating transient closure of Cx43-based gap junctions in normal fibroblasts. Here we show that activated c-Src (c-SrcK+) phosphorylates the COOH-terminal tail of Cx43, both in vitro and in intact cells. Coimmunoprecipitation experiments reveal that Cx43 associates with c-SrcK+ and, to a lesser extent, with wild-type c-Src, but not with kinase-dead c-Src. Mutation of residue Cx43 Tyr265 (Cx43-Y265F mutant) abolishes both tyrosine phosphorylation of Cx43 and its coprecipitation with c-Src. Expression of c-SrcK+ in Rat-1 cells disrupts gap junctional communication. Strikingly, the communication-defective phenotype is bypassed after coexpression of the Cx43-Y265F mutant or a COOH-terminally truncated version of Cx43 (Cx43Δ263) that lacks residue Tyr265. Our results support a model in which activated c-Src phosphorylates the COOH-terminal tail of Cx43 on residue Tyr265, resulting in a stable interaction between both proteins leading to inhibition of gap junctional communication.

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