Modulation of the functional binding sites for TGF-beta on the type II receptor leads to suppression of TGF-beta signaling.
Transforming growth factor-beta (TGF-beta) binds to two different types of serine/threonine kinase receptors termed type II (TbetaR-II) and type I (TbetaR-I). TGF-beta is unable to bind to TbetaR-I in the absence of TbetaR-II, and initiates receptor assembly by binding with high affinity to TbetaR-II. Previous structural analysis of the TGF-beta3-TbetaR-II complex has suggested that two charged amino acid residues, D55 and E142 of TbetaR-II, are binding sites of TGF-beta. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TbetaR-II, resulted in loss of TGF-beta binding and downstream signaling activity. Moreover, we found that 3,5,7,2',4'-pentahydroxyflavone (Morin) inhibits TGF-beta binding to TbetaR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-beta target gene Smad7 induced by TGF-beta. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-beta, including advanced cancers.
Shimanuki
T
T
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.
Hara
T
T
Furuya
T
T
Imamura
T
T
Miyazono
K
K
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001224:Aspartic Acid; D018698:Glutamic Acid