| Itch E 3 ligase mediated regulation of TGF beta signaling by modulating smad 2 phosphorylation . ^^^ Here we show that loss of Itch E 3 ligase in mouse embryonic fibroblasts ( MEFs ) results in reduced susceptibility of TGF beta induced cell growth arrest and decreased phosphorylation of Smad 2 , without apparent alteration in protein levels for Smad 2 , Smad 4 , and Smad 7 in Itch / MEFs . ^^^ Itch promotes ubiquitination of Smad 2 and augments Smad 2 phosphorylation that requires an intact ligase activity of Itch . ^^^ Moreover , Itch facilitates complex formation between TGF beta receptor and Smad 2 and enhances TGF beta induced transcription . ^^^ |