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Oncogene. 2007 May 17;26(23):3311-20. Epub 2006 Dec 4.

Modulation of the functional binding sites for TGF-beta on the type II receptor leads to suppression of TGF-beta signaling.

Author information

1
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.

Abstract

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.

PMID:
17146441
DOI:
10.1038/sj.onc.1210123
[Indexed for MEDLINE]

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