Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.
TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.
Nakao
A
A
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Afrakhte
M
M
Morén
A
A
Nakayama
T
T
Christian
J L
JL
Heuchel
R
R
Itoh
S
S
Kawabata
M
M
Heldin
N E
NE
Heldin
C H
CH
ten Dijke
P
P
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D005246:Feedback; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D015398:Signal Transduction; D051906:Smad7 Protein; D015534:Trans-Activators; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D014981:Xenopus; D029867:Xenopus Proteins
D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins