Smoothened
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Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is not a G protein-coupled receptor[4] (it is instead a GPCR-like receptor) that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the teratogen cyclopamine.[5]
Function
Cellular localization plays an essential role in the function of SMO. Stimulation of the patched receptor by the sonic hedgehog ligand leads to translocation of SMO to the primary cilium. Furthermore, SMO that is mutated in the domain required for ciliary localisation cannot contribute to pathway activation.[6] SMO has also been shown to bind the kinesin motor protein Costal-2 and play a role in the localization of the Ci (Cubitus interruptus transcription factor) complex.[7]
SMO can function as an oncogene. Activating SMO mutations can lead to unregulated activation of the hedgehog pathway and cancer.[8]
Overview of signal transduction pathways involved in apoptosis.
Agonists
- Smoothened agonist (SAG)
- Purmorphamine
- oxysterols including 20(S)-OHC and 20(S)-yne
Antagonists
- Cyclopamine
- Itraconazole
- Vismodegib (Erivedge), a smoothened receptor inhibitor for the treatment of basal-cell carcinoma, being investigated for the treatment of other types of cancer
- SANT-1
- Sonidegib
See also
References
- ↑ "Drugs that physically interact with Smoothened homolog view/edit references on wikidata".
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Ruiz-Gómez A, Molnar C, Holguín H, Mayor F, de Celis JF (April 2007). "The cell biology of Smo signalling and its relationships with GPCRs". Biochimica et Biophysica Acta. 1768 (4): 901–12. doi:10.1016/j.bbamem.2006.09.020. PMID 17094938.
- ↑ Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (August 2000). "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine". Nature. 406 (6799): 1005–9. doi:10.1038/35023008. PMID 10984056.
- ↑ Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (October 2005). "Vertebrate Smoothened functions at the primary cilium". Nature. 437 (7061): 1018–21. doi:10.1038/nature04117. PMID 16136078.
- ↑ Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy PA (November 2003). "Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2". Molecular Cell. 12 (5): 1261–74. doi:10.1016/S1097-2765(03)00426-X. PMID 14636583.
- ↑ Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ (January 1998). "Activating Smoothened mutations in sporadic basal-cell carcinoma". Nature. 391 (6662): 90–2. doi:10.1038/34201. PMID 9422511.
Further reading
- Chen Y, Struhl G (November 1996). "Dual roles for patched in sequestering and transducing Hedgehog". Cell. 87 (3): 553–63. doi:10.1016/S0092-8674(00)81374-4. PMID 8898207.
- Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H, Noll M, Hooper JE, de Sauvage F, Rosenthal A (November 1996). "The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog". Nature. 384 (6605): 129–34. doi:10.1038/384129a0. PMID 8906787.
- Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ (January 1998). "Activating Smoothened mutations in sporadic basal-cell carcinoma". Nature. 391 (6662): 90–2. doi:10.1038/34201. PMID 9422511.
- Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G (May 1998). "Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system". Cancer Research. 58 (9): 1798–803. PMID 9581815.
- Sublett JE, Entrekin RE, Look AT, Reardon DA (May 1998). "Chromosomal localization of the human smoothened gene (SMOH) to 7q32. 3 by fluorescence in situ hybridization and radiation hybrid mapping". Genomics. 50 (1): 112–4. doi:10.1006/geno.1998.5227. PMID 9628830.
- McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB (September 1998). "PTCH gene mutations in invasive transitional cell carcinoma of the bladder". Oncogene. 17 (9): 1167–72. doi:10.1038/sj.onc.1202045. PMID 9764827.
- Chidambaram A, Gerrard B, Hanson M, Dean M (November 1998). "Chromosomal localization of the human and murine orthologues of the Drosophila smoothened gene". Genomics. 53 (3): 416–7. doi:10.1006/geno.1998.5531. PMID 9799615.
- Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ (November 1998). "Characterization of two patched receptors for the vertebrate hedgehog protein family". Proceedings of the National Academy of Sciences of the United States of America. 95 (23): 13630–4. doi:10.1073/pnas.95.23.13630. PMC 24870
. PMID 9811851. - Detmer K, Walker AN, Jenkins TM, Steele TA, Dannawi H (August 2000). "Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling". Blood Cells, Molecules & Diseases. 26 (4): 360–72. doi:10.1006/bcmd.2000.0318. PMID 11042037.
- Long F, Zhang XM, Karp S, Yang Y, McMahon AP (December 2001). "Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation". Development. 128 (24): 5099–108. PMID 11748145.
- Incardona JP, Gruenberg J, Roelink H (June 2002). "Sonic hedgehog induces the segregation of patched and smoothened in endosomes". Current Biology. 12 (12): 983–95. doi:10.1016/S0960-9822(02)00895-3. PMID 12123571.
- Lowrey JA, Stewart GA, Lindey S, Hoyne GF, Dallman MJ, Howie SE, Lamb JR (August 2002). "Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes". Journal of Immunology. 169 (4): 1869–75. doi:10.4049/jimmunol.169.4.1869. PMID 12165511.
- Taipale J, Cooper MK, Maiti T, Beachy PA (August 2002). "Patched acts catalytically to suppress the activity of Smoothened". Nature. 418 (6900): 892–7. doi:10.1038/nature00989. PMID 12192414.
- Katayam M, Yoshida K, Ishimori H, Katayama M, Kawase T, Motoyama J, Kamiguchi H (September 2002). "Patched and smoothened mRNA expression in human astrocytic tumors inversely correlates with histological malignancy". Journal of Neuro-Oncology. 59 (2): 107–15. doi:10.1023/A:1019660421216. PMID 12241103.
- Couvé-Privat S, Bouadjar B, Avril MF, Sarasin A, Daya-Grosjean L (December 2002). "Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients". Cancer Research. 62 (24): 7186–9. PMID 12499255.
- Grachtchouk V, Grachtchouk M, Lowe L, Johnson T, Wei L, Wang A, de Sauvage F, Dlugosz AA (June 2003). "The magnitude of hedgehog signaling activity defines skin tumor phenotype". The EMBO Journal. 22 (11): 2741–51. doi:10.1093/emboj/cdg271. PMC 156767. PMID 12773389.
- Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ (December 2004). "Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2". Science. 306 (5705): 2257–60. doi:10.1126/science.1104135. PMID 15618519.
- Byrne EF, Sircar R, Miller PS, Hedger G, Luchetti G, Nachtergaele S, Tully MD, Mydock-McGrane L, Covey DF, Rambo RP, Sansom MS, Newstead S, Rohatgi R (July 2016). "Structural basis of Smoothened regulation by its extracellular domains". Nature. 535 (7613): 517–22. doi:10.1038/nature18934. PMID 27437577.
External links
- "Frizzled Receptors: SMO". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- SMO protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
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