5zok

Structural highlights

Disease

[SMAD1_HUMAN] Defects in SMAD1 may be a cause of primary pulmonary hypertension (PPH1) [MIM:178600]. A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.^[1] [MAN1_HUMAN] Isolated osteopoikilosis;Buschke-Ollendorff syndrome;12q14 microdeletion syndrome;Melorheostosis with osteopoikilosis. The disease is caused by mutations affecting the gene represented in this entry.

Function

[SMAD1_HUMAN] Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.^[2] [MAN1_HUMAN] Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.^{[3] [4]}

References

1. ↑ Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, Bradshaw TY, Southgate L, Lee GJ, Jackson I, Lord GM, Gibbs JS, Wilkins MR, Ohta-Ogo K, Nakamura K, Girerd B, Coulet F, Soubrier F, Humbert M, Morrell NW, Trembath RC, Machado RD. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat. 2011 Dec;32(12):1385-9. doi: 10.1002/humu.21605. Epub 2011 Oct 11. PMID:21898662 doi:10.1002/humu.21605
2. ↑ Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA, Paralkar V, Wang T. A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs). BMC Cell Biol. 2002 Jun 21;3:15. PMID:12097147
3. ↑ Lin F, Morrison JM, Wu W, Worman HJ. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet. 2005 Feb 1;14(3):437-45. doi: 10.1093/hmg/ddi040. Epub 2004 Dec, 15. PMID:15601644 doi:http://dx.doi.org/10.1093/hmg/ddi040
4. ↑ Pan D, Estevez-Salmeron LD, Stroschein SL, Zhu X, He J, Zhou S, Luo K. The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. J Biol Chem. 2005 Apr 22;280(16):15992-6001. doi: 10.1074/jbc.M411234200. Epub, 2005 Jan 12. PMID:15647271 doi:http://dx.doi.org/10.1074/jbc.M411234200