Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors.
Members of the transforming growth factor-beta (TGF-beta) family transmit signals from membrane to nucleus via intracellular proteins known as Smads. A subclass of Smad proteins has recently been identified that antagonize, rather than transduce, TGF-beta family signals. Smad7, for example, binds to and inhibits signaling downstream of TGF-beta receptors. Here we report that the C-terminal MAD homology domain of murine Smad7 (mSmad7) is sufficient for both of these activities. In addition, we show that mSmad7 interacts with activated bone morphogenetic protein (BMP) type I receptors (BMPR-Is), inhibits BMPR-I-mediated Smad phosphorylation, and phenocopies the effect of known BMP antagonists when overexpressed in ventral cells of Xenopus embryos. Xenopus Smad7 (XSmad7, previously termed Smad8) and mSmad7 are nearly identical within their bioactive C-domain, but have quite distinct N-domains. We found that XSmad7, similar to mSmad7, interacted with BMP and TGF-beta type I receptors and inhibited receptor-mediated phosphorylation of downstream signal-transducing Smads. However, XSmad7 is a less efficient inhibitor of TbetaR-I-mediated responses in mammalian cells than is mSmad7. Furthermore, overexpression of XSmad7 in Xenopus embryos produces patterning defects that are not observed following overexpression of mSmad7, suggesting that mSmad7 and XSmad7 may preferentially target distinct signaling pathways. Our results are consistent with the possibility that the C-domain of antagonistic Smads is an effector domain whereas the N-domain may confer specificity for distinct signaling pathways.
Souchelnytskyi
S
S
Ludwig Institute for Cancer Research, Biomedical Center, S-751 24 Uppsala, Sweden.
Nakayama
T
T
Nakao
A
A
Morén
A
A
Heldin
C H
CH
Christian
J L
JL
ten Dijke
P
P
D000818:Animals; D019521:Body Patterning; D052004:Bone Morphogenetic Protein Receptors; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008907:Mink; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins
D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D029867:Xenopus Proteins; D052004:Bone Morphogenetic Protein Receptors