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J. Cell Biol.,
Volume 144, Number 5, March 8, 1999 1033-1045
Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York 14260
Suppression of gap-junctional communication by various protein kinases, growth factors, and oncogenes frequently correlates with enhanced mitogenesis. The oncogene v-src appears to cause acute closure
of gap junction channels. Tyr265 in the COOH-terminal tail of connexin 43 (Cx43) has been implicated as a potential target of v-src, although v-src action has also
been associated with changes in serine phosphorylation. We have investigated the mechanism of this acute
regulation through mutagenesis of Cx43 expressed in
Xenopus laevis oocyte pairs. Truncations of the COOH-terminal domain led to an almost complete loss of
response of Cx43 to v-src, but this was restored by coexpression of the independent COOH-terminal polypeptide. This suggests a ball and chain gating mechanism, similar to the mechanism proposed for pH gating of
Cx43, and K+ channel inactivation. Surprisingly, we
found that v-src mediated gating of Cx43 did not require the tyrosine site, but did seem to depend on the
presence of two potential SH3 binding domains and the
mitogen-activated protein (MAP) kinase phosphorylation sites within them. Further point mutagenesis and
pharmacological studies in normal rat kidney (NRK)
cells implicated MAP kinase in the gating response to
v-src, while the stable binding of v-src to Cx43 (in part
mediated by SH3 domains) did not correlate with its
ability to mediate channel closure. This suggests a
common link between closure of gap junctions by v-src
and other mitogens, such as EGF and lysophosphatidic
acid (LPA).
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