Mechanism for mutational inactivation of the tumor suppressor Smad2

Molecular and Cellular Biology
C PrunierA Atfi

Abstract

Transforming growth factor beta (TGF-beta) is a potent natural antiproliferative agent that plays an important role in suppressing tumorigenicity. In numerous tumors, loss of TGF-beta responsiveness is associated with inactivating mutations that can occur in components of this signaling pathway, such as the tumor suppressor Smad2. Although a general framework for how Smads transduce TGF-beta signals has been proposed, the physiological relevance of alterations of Smad2 functions in promoting tumorigenesis is still unknown. Here, we show that expression of Smad2.P445H, a tumor-derived mutation of Smad2 found in human cancer, suppresses the ability of the Smads to mediate TGF-beta-induced growth arrest and transcriptional responses. Smad2.P445H is phosphorylated by the activated TGF-beta receptor at the carboxy-terminal serine residues and associates with Smad3 and Smad4 but is unable to dissociate from the receptor. Upon ligand-induced phosphorylation, Smad2.P445H interacts stably with wild-type Smad2, thereby blocking TGF-beta-induced nuclear accumulation of wild-type Smad2 and Smad2-dependent transcription. The ability of the Smad2.P445H to block the nuclear accumulation of wild-type Smad2 protein reveals a new mechanism for l...Continue Reading

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Citations

Sep 5, 2006·Cancer Metastasis Reviews·Sonia B Jakowlew
Jan 26, 2011·Molecular and Cellular Biology·Michèle SabbahGérard Redeuilh
Dec 23, 2011·Journal of the American Medical Informatics Association : JAMIA·Xiaoping LiuLuonan Chen
Aug 15, 2006·Biochimica Et Biophysica Acta·Katerina Pardali, Aristidis Moustakas
Oct 5, 2001·Nature Genetics·R DerynckA Balmain
Jun 11, 2005·The Journal of Biological Chemistry·François LallemandAzeddine Atfi
Dec 13, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nathalie FerrandAzeddine Atfi
Jul 31, 2001·The Journal of Biological Chemistry·A MazarsA Atfi
Aug 1, 2002·The Journal of Biological Chemistry·Jérôme LafontCécile Martinerie
May 30, 2002·The Journal of Biological Chemistry·Marcia PessahAzeddine Atfi
May 11, 2004·The Journal of Biological Chemistry·Lucile AbécassisMarie-Françoise Bourgeade
Apr 18, 2003·The Journal of Biological Chemistry·Emmanuelle DumontNathalie Théret
Jun 9, 2020·Molecular Biology Reports·Parsa Sanjana HaqueMd Saiful Islam
Mar 17, 2018·Experimental and Therapeutic Medicine·Yong-Hui ZhangYong Wei

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