Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling.
Tob inhibits bone morphogenetic protein (BMP) signaling by interacting with receptor-regulated Smads in osteoblasts. Here we provide evidence that Tob also interacts with the inhibitory Smads 6 and 7. A yeast two-hybrid screen identified Smad6 as a protein interacting with Tob. Tob co-localizes with Smad6 at the plasma membrane and enhances the interaction between Smad6 and activated BMP type I receptors. Furthermore, we have isolated Xenopus Tob2, and show that it cooperates with Smad6 in inducing secondary axes when expressed in early Xenopus embryos. Finally, Tob and Tob2 cooperate with Smad6 to inhibit endogenous BMP signaling in Xenopus embryonic explants and in cultured mammalian cells. Our results provide both in vitro and in vivo evidence that Tob inhibits endogenous BMP signaling by facilitating inhibitory Smad functions.
Yoshida
Yutaka
Y
Department of Oncology, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
von Bubnoff
Andreas
A
Ikematsu
Naoko
N
Blitz
Ira L
IL
Tsuzuku
Junko K
JK
Yoshida
Eri H
EH
Umemori
Hisashi
H
Miyazono
Kohei
K
Yamamoto
Tadashi
T
Cho
Ken W Y
KW
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000939:Epitopes; D017930:Genes, Reporter; D015151:Immunoblotting; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051905:Smad6 Protein; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D014981:Xenopus; D029867:Xenopus Proteins
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000939:Epitopes; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051905:Smad6 Protein; C497805:Smad6 protein, Xenopus; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; C497807:Smad7 protein, mouse; C490903:Tob1 protein, mouse; C485732:Tob2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins