Human Molecular Genetics Advance Access published online on December 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi040
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1 Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
* To whom correspondence should be addressed. MAN1 (also known as LEMD3) is an integral protein of the inner nuclear membrane. Recently, mutations in MAN1 have been shown to result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. We show that the nucleoplasmic, carboxyl-terminal domain of human MAN1 binds to Smad2 and Smad3 and antagonizes signaling by transforming growth factor-ß (TGF-ß). In a yeast two-hybrid screen using the carboxyl-terminal domain of MAN1 as bait, 8 positive clones were obtained that encoded Smad3. In direct two-hybrid assays, this portion of MAN1 bound to Smad2 and Smad3. In glutathione-S-transferase precipitation assays, the carboxyl-terminal domain of MAN1 bound to Smad2 and Smad3 under stringent conditions. Antibodies against MAN1 were able to co-immunoprecipiate Smad2 from cells, demonstrating they reside in the same complex in vivo. TGF-ß treatment stimulated transcription from a reporter gene in control cells but reporter gene stimulation was significantly inhibited in cells overexpressing MAN1 or its carboxyl-terminal domain but not its amino-terminal domain. TGF-ß-induced cell proliferation arrest was also inhibited in stable cell lines overexpressing MAN1. These results show that the nuclear envelope regulates a signal transduction pathway and have implications for how mutations in nuclear envelope proteins cause different human diseases.
Article
MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-ß signaling
2 Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, 630 West 168th St., 10th Floor, Rm. 508, New York, NY 10032
Howard J. Worman, E-mail: hjw14{at}columbia.edu
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