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

Transforming growth factor-b (TGF-b) binds to two different types of serine/threonine kinase receptors termed type II (TbR-II) and type I (TbR-I). TGF-b is unable to bind to TbR-I in the absence of TbR-II, and initiates receptor assembly by binding with high affinity to TbR-II. Previous structural analysis of the TGF-b3-TbR-II complex has suggested that two charged amino acid residues, D55 and E142 of TbR-II, are binding sites of TGF-b. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TbR-II, resulted in loss of TGF-b binding and downstream signaling activity. Moreover, we found that 3,5,7,2',4'-pentahydroxyflavone (Morin) inhibits TGF-b binding to TbR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-b target gene Smad7 induced by TGF-b. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-b, including advanced cancers.Oncogene (2007) 26, 3311-3320. doi:10.1038/sj.onc.1210123; published online 4 December 2006