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Coregulation of Multiple Signaling Mechanisms in pp60v-Src-Induced Closure of Cx43 Gap Junction Channels

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Abstract

Attenuation in gap junctional coupling has consistently been associated with induction of rapid or synchronous cell division in normal and pathological conditions. In the case of the v-src oncogene, gating of Cx43 gap junction channels has been linked to both direct phosphorylation of tyrosines (Y247 and 265) and phosphorylation of the serine targets of Erk1/2 (S255, 279 and 282) on the cytoplasmic C-terminal domain of Cx43. However, only the latter has been associated with acute, rather than chronic, gating of the channels immediately after v-src expression, a process that is mediated through a “ball-and-chain” mechanism. In this study we show that, while ERK1/2 is necessary for acute closure of gap junction channels, it is not sufficient. Rather, multiple pathways converge to regulate Cx43 coupling in response to expression of v-src, including parallel signaling through PKC and MEK1/2, with additional positive and negative regulatory effects mediated by PI3 kinase, distinguished by the involvement of Akt.

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Acknowledgments

Te authors are grateful to Mario Delmar and Steve Taffett for providing various Cx43 mutants, Elissavett Kardami for the PKC constructs, Marilyn Resh for provision of the v-src construct and Natalie Ahn for providing the CA-MEK1 construct. The authors’ thank Mary Merritt and Eileen Kasperek for technical assistance, Sandra A. Mathis for help in compiling the manuscript and Edward A. Kalmykov for assistance in preparing the figures for submission. This study was supported by National Institutes of Health grant CA048049 (to B. J. N.).

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  1. Siddhartha S. Mitra

    Present address: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 09304, USA

  2. Ji Xu

    Present address: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA

Authors and Affiliations

  1. Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Siddhartha S. Mitra, Ji Xu & Bruce J. Nicholson

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  1. Siddhartha S. Mitra
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Correspondence to Bruce J. Nicholson.

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Mitra, S.S., Xu, J. & Nicholson, B.J. Coregulation of Multiple Signaling Mechanisms in pp60v-Src-Induced Closure of Cx43 Gap Junction Channels. J Membrane Biol 245, 495–506 (2012). https://doi.org/10.1007/s00232-012-9500-0

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