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Vol. 18, Issue 6, 2264-2273, June 2007

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Cx43 Mediates TGF- Signaling through Competitive Smads Binding to Microtubules

Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

Submitted December 4, 2006; Revised March 21, 2007; Accepted April 2, 2007
Monitoring Editor: Ben Margolis

Transforming growth factor- (TGF-) superfamily members play an important role in growth, differentiation, adhesion, apoptosis, and development in many species from insects and worms to vertebrates. Recently, TGF- signaling has been demonstrated to be negatively regulated by microtubules (MTs), which anchor endogenous Smad2/3 to cytosol and also directly interact with connexin43 (Cx43), and the activity of TGF- is mediated by Cx43. However, the mechanism underlying the intracellular regulation of TGF- activity by Cx43 remains unknown. Here, we found that the functional link between TGF- activation and Cx43 is mediated by interactions among Smad2/3, MTs, and Cx43. We confirmed that Cx43 competes with Smad2/3 for binding to MTs, which Cx43 specifically induces release of Smad2/3 from MTs and increases phospho-Smad2 and which, as a result, Smad2/3 and Smad4 are accumulated in the nucleus, leading to activation of the transcription of target genes. Consistently, knockdown of the endogenous Cx43 activity with double-strand RNA (dsRNA) in HL1 cardiomyocytes and Cx43 knockout mice cardiomyocytes consistently show the opposite effect. Our findings demonstrate a novel mechanism for Cx43 positive regulation of TGF- function.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Ping Dai (dping{at}koto.kpu-m.ac.jp) or Tetsuro Takamatsu (ttakam{at}koto.kpu-m.ac.jp)

Abbreviations used: Cx43, connexin 43; MT, microtubule.

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