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

Transforming growth factor-beta (TGF-beta) binds to two different types of serine/threonine kinase receptors termed type II (T beta R-II) and type I (T beta R-I). TGF-beta is unable to bind to T beta R-I in the absence of T beta R-II, and initiates receptor assembly by binding with high affinity to T beta beta R-II. Previous structural analysis of the TGF-beta 3-T beta R-II complex has suggested that two charged amino acid residues, D55 and E142 of T beta R-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 T beta R-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 T beta R-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.