Regulation of TGF-ß Signal Transduction

Zhao, Bing; Chen, Ye-Guang

Upon being phosphorylated by T RII, the activated T RI recruits and phosphorylates Smad2/3 at the C-terminal (Figure 3(a) ). Various proteins associated with the receptors complex have been reported to regulate R-Smad recruitment [90] , such as SARA and endofin as mentioned above. BMP and activin membrane-bound inhibitor (BAMBI) has been reported as a general antagonist of TGF-family members. Acting as a pseudoreceptor, BAMBI interferes with the interaction between type I and type II receptors of the TGFfamily [91] . In addition to blocking the heterocomplex formation of TGF-receptors, our recent work showed that BAMBI cooperates with Smad7 to inhibit TGF-signaling [92] . BAMBI can form a ternary complex with Smad7 and T RI and inhibit the interaction between T RI and Smad3, which impairs Smad3 activation (Figure 3(b) ). Besides, we also found that p21-activated kinase 2 (PAK2) can directly phosphorylate Smad2 at Ser417, which interferes with the T RI-Smad2 association and thus blocks TGF--induced Smad2 activation and signaling [93] . Phosphorylated Smad2/3 binds Smad4 to form a Smad heterocomplex, which mediates downstream signal transduction. We have reported that the FYVE domain-containing protein endofin can interact with both T RI and Smad4 [39] . As a scaffold protein, endofin recruits Smad4 to T RI in early endosomes and facilitates the association of receptoractivated Smad2 with Smad4 (Figure 3(a) ).