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MBC in Press, published online ahead of print April 11, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1064

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Submitted on December 4, 2006
Revised on March 21, 2007
Accepted on April 2, 2007

Cx43 Mediates TGF-{beta} Signaling through Competitive Smads Binding to Microtubules

Ping Dai, Takuo Nakagami, Hideo Tanaka, Toshiaki Hitomi, and Tetsuro Takamatsu

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

Monitoring Editor: Ben Margolis

Transforming growth factor-{beta} (TGF-{beta}) superfamily members play an important role in growth, differentiation, adhesion, apoptosis and development in many species from insects and worms to vertebrates. Recently, TGF-{beta} signaling has been demonstrated to negatively regulated by microtubules (MTs), which anchor endogenous Smad2/3 to cytosol and also directly interact with connexin43 (Cx43), and the activity of TGF-{beta} is mediated by Cx43. However, the mechanism underlying the intracellular regulation of TGF-{beta} activity by Cx43 remains unknown. Here, we found that the functional link between TGF-{beta} activation and Cx43 is mediated by interactions among Smad2/3, microtubules (MTs) and Cx43. We confirmed that Cx43 competes with Smad2/3 for binding to MTs, that Cx43 specifically induces release of Smad2/3 from MTs and increases phospho-Smad2, and that, 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 (ds-RNA) 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-{beta} function.

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




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Y. Nakano, M. Oyamada, P. Dai, T. Nakagami, S. Kinoshita, and T. Takamatsu
Connexin43 Knockdown Accelerates Wound Healing but Inhibits Mesenchymal Transition after Corneal Endothelial Injury In Vivo
Invest. Ophthalmol. Vis. Sci., January 1, 2008; 49(1): 93 - 104.
[Abstract] [Full Text] [PDF]


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