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J. Biol. Chem., Vol. 282, Issue 13, 9688-9695, March 30, 2007

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Endofin, a FYVE Domain Protein, Interacts with Smad4 and Facilitates Transforming Growth Factor- Signaling^*

Ye-Guang Chen¹, Zhi Wang, Jing Ma, Long Zhang, and Zhongxian Lu

From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China and the Department of Medicine and Biological Chemistry, College of Medicine, University of California, Irvine, California 92697

Transforming growth factor- (TGF-) signaling is facilitated by scaffold proteins such as SARA (Smad anchor for receptor activation). Endofin, a member of the FYVE domain protein family, has been suggested to regulate membrane trafficking. In this study, we report that endofin functions as a scaffold protein to facilitate TGF- signaling. Overexpression of endofin FYVE domain-deletion mutants inhibited TGF--induced expression of CAGA-luciferase. Knockdown of endogenous endofin expression by RNA interference specifically led to reduction of the transcriptional responses of TGF-, but had no effect on BMP- or Wnt1-induced reporter expression. Furthermore, in endofin small interfering RNA-expressing stable cells, TGF--mediated expression of plasminogen activator inhibitor-1 and p21^Cip1 was significantly reduced, and TGF--promoted apoptosis was also impaired. We further showed that endofin could interact with Smad4 and TGF- type I receptors. Reduction of endogenous endofin expression resulted in a decrease of TGF--induced Smad2 phosphorylation and Smad2-Smad4 complex formation. Together, our findings suggest that endofin facilitates TGF- signaling as a scaffold protein to promote the R-Smad-Smad4 complex formation by bringing Smad4 to the proximity of the receptor complex.

Received for publication, December 21, 2006 , and in revised form, February 1, 2007.

^* This work was supported in part by National Natural Science Foundation of China Grants 30125021 and 30430360, and 973 Program Grants 2004CB720002 and 2006CB910100. 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.

¹ Chueng Kong Scholar. To whom correspondence should be addressed. Tel.: 86-10-62795-184; Fax: 86-10-6279-4376; E-mail: ygchen{at}tsinghua.edu.cn.

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