STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling

Smad proteins play a key role in the intracellular signaling of the transfo rming growth factor beta (TGF-beta) superfamily of extracellular polypeptid es that initiate signaling from the cell surface through serine/threonine k inase receptors. A subclass of Smad proteins, including Smad6 and Smad7, ha s been shown to function as intracellular antagonists of TGF-beta family si gnaling. We have previously reported the identification of a WD40 repeat pr otein, STRAP, that associates with both type I and type II TGF-beta recepto rs and that is involved in TGF-beta signaling. Here we demonstrate that STR AP synergizes specifically with Smad7, but not with Smad6, in the inhibitio n of TGF-beta-induced transcriptional responses. STRAP does not show cooper ation with a C-terminal deletion mutant of Smad7 that does not bind with th e receptor and consequently has no inhibitory activity. STRAP associates st ably with Smad7, but not crith the Smad7 mutant. STRAP recruits Smad7 to th e activated type I receptor and forms a complex. Moreover, STRAP stabilizes the association between Smad7 and the activated receptor, thus assisting S mad7 in preventing Smad2 and Smad3 access to the receptor. STRAP interacts with Smad2 and Smad3 but does not cooperate functionally with these Smads t o transactivate TGF-beta-dependent transcription. The C terminus of STRAP i s required for its phosphorylation in vivo, which is dependent on the TGF-b eta receptor kinases. Thus, we describe a mechanism to explain how STRAP an d Smad7 function synergistically to block TGF-beta-induced transcriptional activation.