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J. Biol. Chem., Vol. 280, Issue 20, 19925-19936, May 20, 2005

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Connexin43 Associated with an N-cadherin-containing Multiprotein Complex Is Required for Gap Junction Formation in NIH3T3 Cells^*

Chih-Jen Wei, Richard Francis, Xin Xu, and Cecilia W. Lo

From the Laboratory of Developmental Biology, NHLBI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

Previous studies have indicated an intimate linkage between gap junction and adherens junction formation. It was suggested this could reflect the close membrane-membrane apposition required for junction formation. In NIH3T3 cells, we observed the colocalization of connexin43 (Cx431) gap junction protein with N-cadherin, p120, and other N-cadherin-associated proteins at regions of cell-cell contact. We also found that Cx431, N-cadherin, and N-cadherin-associated proteins were coimmunoprecipitated by antibodies to either Cx431, N-cadherin, or various N-cadherin-associated proteins. These findings suggest that Cx431 and N-cadherin are coassembled in a multiprotein complex containing various N-cadherin-associated proteins. Studies using siRNA knockdown indicated that cell surface expression of Cx431 required N-cadherin, and conversely, N-cadherin cell surface expression required Cx431. Pulse-chase labeling and cell surface biotinylation experiments indicated that in the absence of N-cadherin, Cx431 cell surface trafficking is blocked. Surprisingly, siRNA knockdown of p120, an N-cadherin-associated protein known to modulate cell surface turnover of N-cadherin, reduced N-cadherin cell surface expression without altering Cx431 expression. These observations suggest that in contrast to the coregulated cell surface trafficking of Cx431 and N-cadherin, N-cadherin turnover at the cell surface may be regulated independently of Cx431. Functional studies showed gap junctional communication is reduced and cell motility inhibited with N-cadherin or Cx431 knockdown, consistent with the observed loss of both gap junction and cadherin contacts with either knockdown. Overall, these studies indicate that the intracellular coassembly of connexin and cadherin is required for gap junction and adherens junction formation, a process that likely underlies the intimate association between gap junction and adherens junction formation.

Received for publication, November 15, 2004 , and in revised form, February 23, 2005.

^* This work was supported by National Institutes of Health Grant Z01-HL005701. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 50 South Dr. MSC 8019, Rm. 4537, Bethesda, MD 20892-8019. Tel.: 301-451-8041; Fax: 301-480-4581; E-mail: loc{at}nhlbi.nih.gov.

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