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Molecular and Cellular Biology, December 2000, p. 9346-9355, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hgs (Hrs), a FYVE Domain Protein, Is Involved in Smad Signaling through Cooperation with SARA

Shigeto Miura,1,2 Toshikazu Takeshita,1 Hironobu Asao,1 Yutaka Kimura,1 Kazuko Murata,1,2 Yoshiteru Sasaki,1 Jun-Ichi Hanai,3 Hideyuki Beppu,3 Tomoo Tsukazaki,4 Jeffrey L. Wrana,5 Kohei Miyazono,3 and Kazuo Sugamura1,2,*

Department of Microbiology and Immunology, Tohoku University School of Medicine, Aoba-ku,1 and CREST Program of the Japan Science and Technology Corporation,2 Sendai 980-8575, Department of Biochemistry, The Cancer Institute, Tokyo 170-8456,3 and Department of Nature Medicine Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki 852-8523,4 Japan, and Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X55

Received 18 July 2000/Accepted 27 September 2000

Smad proteins are effector molecules that transmit signals from the receptors for the transforming growth factor beta  (TGF-beta ) superfamily to the nucleus; of the Smad proteins, Smad2 and Smad4 are essential components for mouse early embryogenesis. We demonstrated that Hgs, a FYVE domain protein, binds to Smad2 in its C-terminal half and cooperates with another FYVE domain protein, the Smad anchor for receptor activation (SARA), to stimulate activin receptor-mediated signaling through efficient recruitment of Smad2 to the receptor. Furthermore, a LacZ knock-in allele of the C-terminal half-deletion mutant of mouse Hgs was created by gene targeting. The introduced mutation causes an embryonic lethality between embryonic days 8.5 and 10.5. Mutant cells showed significantly decreased responses to stimulation with activin and TGF-beta . These findings suggest that the two FYVE domain proteins, Hgs and SARA, are prerequisites for receptor-mediated activation of Smad2.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8096. Fax: 81-22-717-8097. E-mail: sugamura{at}mail.cc.tohoku.ac.jp.

Molecular and Cellular Biology, December 2000, p. 9346-9355, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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