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- Title
Negative regulation of transforming growth factor-ß(TGF-ß) signaling by WW domain-containing protein 1 (WWP1).
- Authors
Komura, Akiyoshi; Imamura, Takeshi; Saitoh, Masao; Yoshida, Yoko; Yamori, Takao; Miyazono, Kohei; Miyazawa, Keiji
- Abstract
Smad7 negatively regulates transforming growth factor (TGF)-ßsuperfamily signaling by binding to activated type I receptors, thereby preventing the phosphorylation of receptor-regulated Smads (R-Smads), as well as by recruiting HECT-type E3 ubiquitin ligases to degrade type I receptors through a ubiquitin-dependent mechanism. To elucidate the regulatory mechanisms of TGF-ßsignaling, we searched for novel members of proteins that interact with Smad7 using a yeast two-hybrid system. One of the proteins identified was the WW domain-containing protein 1 (WWP1) that is structurally related to Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases for Smads and TGF-ßsuperfamily receptors. Using a TGF-ß-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-ß. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-ßtype I receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, WWP1 inhibited phosphorylation of Smad2 induced by TGF-ß. WWP1 thus negatively regulates TGF-ßsignaling in cooperation with Smad7. However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN. Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs.Oncogene (2004) 23, 6914-6923. doi:10.1038/sj.onc.1207885 Published online 28 June 2004
- Subjects
GROWTH factors; CHEMICAL reactions; BIOMOLECULES; CELL culture; CELL lines; CYTOKINES
- Publication
Oncogene, 2004, Vol 23, Issue 41, p6914
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207885