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J. Biol. Chem., Vol. 279, Issue 28, 29681-29690, July 9, 2004

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Atrophin-1-interacting Protein 4/Human Itch Is a Ubiquitin E3 Ligase for Human Enhancer of Filamentation 1 in Transforming Growth Factor- Signaling Pathways^*

Libing Feng, Susana Guedes, and Tongwen Wang

From the Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101

Atrophin-1-interacting protein 4 (AIP4) is the human homolog of the mouse Itch protein (hItch), an E3 ligase for Notch and JunB. Human enhancer of filamentation 1 (HEF1) has been implicated in signaling pathways such as those mediated by integrin, T cell receptor, and B cell receptor and functions as a multidomain docking protein. Recent studies suggest that HEF1 is also involved in the transforming growth factor- (TGF-) signaling pathways, by interacting with Smad3, a key signal transducer downstream of the TGF- type I receptor. The interaction of Smad3 with HEF1 induces HEF1 proteasomal degradation, which was further enhanced by TGF- stimulation. The detailed molecular mechanisms of HEF1 degradation regulated by Smad3 were poorly understood. Here we report our studies that demonstrate the function of AIP4 as an ubiquitin E3 ligase for HEF1. AIP4 forms a complex with both Smad3 and HEF1 through its WW domains in a TGF--independent manner and regulates HEF1 ubiquitination and degradation, which can be enhanced by TGF- stimulation. These findings reveal a new mechanism for Smad3-regulated proteasomal degradation events and also broaden the network of cross-talk between the TGF- signaling pathway and those involving HEF1 and AIP4.

Received for publication, March 23, 2004

^* This work was supported by American Cancer Society Research Scholar Grant RSG-01-184-01-TBE (to T. W.) and the institution fund from the Benaroya Research Institute at Virginia Mason. 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: Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave., Seattle, WA 98101. Tel.: 206-223-6846; Fax: 206-223-7543; E-mail: wangt{at}vmresearch.org.

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