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Molecular and Cellular Biology, August 2001, p. 5132-5141, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5132-5141.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Axin Facilitates Smad3 Activation in the Transforming Growth Factor beta  Signaling Pathway

Masao Furuhashi,1,2 Ken Yagi,1 Hideki Yamamoto,3 Yoichi Furukawa,4 Shinji Shimada,2 Yusuke Nakamura,4 Akira Kikuchi,3 Kohei Miyazono,1,5,* and Mitsuyasu Kato1

Department of Biochemistry, The Japanese Foundation for Cancer Research (JFCR) Cancer Institute, Toshima-ku, Tokyo 170-8455,1 Department of Dermatology, Yamanashi Medical College, Yamanashi 490-3898,2 Department of Biochemistry, Hiroshima University School of Medicine, Hiroshima 734-8551,3 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639,4 and Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033,5 Japan

Received 13 December 2000/Returned for modification 17 January 2001/Accepted 9 May 2001

Axin acts as a negative regulator in Wnt signaling through interaction with various molecules involved in this pathway, including beta -catenin, adenomatous polyposis coli, and glycogen synthase kinase 3beta . We show here that Axin also regulates the effects of Smad3 on the transforming growth factor beta  (TGF-beta ) signaling pathway. In the absence of activated TGF-beta receptors. Axin physically interacted with Smad3 through its C-terminal region located between the beta -catenin binding site and Dishevelled-homologous domain. An Axin homologue, Axil (also called conductin), also interacted with Smad3. In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo. Upon receptor activation, Smad3 was strongly phosphorylated by TGF-beta type I receptor (Tbeta R-I) in the presence of Axin, and dissociated from Tbeta R-I and Axin. Moreover, the transcriptional activity of TGF-beta was enhanced by Axin and repressed by an Axin mutant which is able to bind to Smad3. Axin may thus function as an adapter of Smad3, facilitating its activation by TGF-beta receptors for efficient TGF-beta signaling.

* Corresponding author. Mailing address: Department of Biochemistry, The JFCR Cancer Institute, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. Phone: 81-3-5394-3866. Fax: 81-3-3918-0342. E-mail: miyazono-ind{at}umin.ac.jp.

Molecular and Cellular Biology, August 2001, p. 5132-5141, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5132-5141.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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