Regulation of TGF-ß Signal Transduction

Zhao, Bing; Chen, Ye-Guang

TGF-receptors localized in lipid raft/caveolae and caveolin-1-positive vesicles undergo ubiquitination-mediated degradation [36, 68, 69] . Recruitment of the WW-HECT-type E3 ubiquitin ligases Smurf1, Smurf2, NEDD4-2 and WWP1 to T RI is essential for its ubiquitination, in which process Smad7 acts as a critical adaptor [70] . Smad7 can bind to T RI and HECT domain-containing E3 ligases and thus facilitate the assembly of the T RI-Smad7-E3 complex, in which both T RI and Smad7 are ubiquitinated and degradated [71] [72] [73] [74] [75] ( Figure 2(a) ). T RI ubiquitination is finely controlled by multiple proteins, one of which we found is TGF--stimulated clone 22 (TSC-22). TSC-22, which was first reported as a TGF--upregulated gene in MC3T3E1 mouse osteoblastic cells, contains a leucine zipper-like structure and a nuclear export signal [76] . Accumulated evidence indicates that TSC-22 has an antiproliferative activity and is downregulated in several types of tumor cells [77] [78] [79] [80] [81] [82] . We identified TSC-22 as a T RI-binding partner using a yeast two-hybrid screen [83] . As a TGF-target, TSC-22 can disrupt the binding of Smad7/Smurfs with T RI and therefore decrease the ubiquitination and degradation of the receptor, leading to enhanced TGF-signaling [83] (Figure 2(b) ). This positivefeedback loop may be involved in myocardial fibrosis as an elevated TSC-22 level was correlated with TGF-signaling