Smoothened

Smoothened, frizzled class receptor
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4JKV​, 4N4W​, 4O9R​, 4QIM​, 4QIN​
Identifiers
Symbols	SMO ; FZD11; Gx; SMOH
External IDs	OMIM: 601500 MGI: 108075 HomoloGene: 4115 IUPHAR: 239 ChEMBL: 5971 GeneCards: SMO Gene
Gene ontology Molecular function • G-protein coupled receptor activity • patched binding • protein binding • drug binding • Wnt-protein binding • Wnt-activated receptor activity Cellular component • Golgi apparatus • plasma membrane • caveola • integral component of membrane • endocytic vesicle membrane • intracellular membrane-bounded organelle • ciliary membrane • extracellular exosome • primary cilium • ciliary tip Biological process • negative regulation of transcription from RNA polymerase II promoter • vasculogenesis • osteoblast differentiation • in utero embryonic development • cell fate specification • neural crest cell migration • heart looping • positive regulation of neuroblast proliferation • positive regulation of mesenchymal cell proliferation • determination of left/right asymmetry in lateral mesoderm • type B pancreatic cell development • G-protein coupled receptor signaling pathway • smoothened signaling pathway • positive regulation of hh target transcription factor activity • ventral midline determination • midgut development • anterior/posterior pattern specification • positive regulation of gene expression • negative regulation of gene expression • cerebellar cortex morphogenesis • thalamus development • dorsal/ventral neural tube patterning • smoothened signaling pathway involved in ventral spinal cord patterning • smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation • central nervous system neuron differentiation • cerebral cortex development • negative regulation of epithelial cell differentiation • hair follicle morphogenesis • protein localization to nucleus • multicellular organism growth • non-canonical Wnt signaling pathway • positive regulation of multicellular organism growth • positive regulation of protein import into nucleus • odontogenesis of dentin-containing tooth • negative regulation of apoptotic process • negative regulation of DNA binding • positive regulation of smoothened signaling pathway • positive regulation of transcription from RNA polymerase II promoter • positive regulation of organ growth • astrocyte activation • skeletal muscle fiber development • forebrain morphogenesis • homeostasis of number of cells within a tissue • positive regulation of epithelial cell proliferation • protein stabilization • myoblast migration • negative regulation of hair follicle development • canonical Wnt signaling pathway • detection of cell density by contact stimulus involved in contact inhibition • atrial septum morphogenesis • mammary gland epithelial cell differentiation • epithelial-mesenchymal cell signaling • somite development • pancreas morphogenesis • left/right axis specification • cellular response to cholesterol • renal system development • mesenchymal to epithelial transition involved in metanephric renal vesicle formation • positive regulation of branching involved in ureteric bud morphogenesis • regulation of stem cell maintenance • regulation of heart morphogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6608	319757
Ensembl	ENSG00000128602	ENSMUSG00000001761
UniProt	Q99835	P56726
RefSeq (mRNA)	NM_005631	NM_176996
RefSeq (protein)	NP_005622	NP_795970
Location (UCSC)	Chr 7: 129.19 – 129.21 Mb	Chr 6: 29.74 – 29.76 Mb
PubMed search

Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is not a G protein-coupled receptor^[1] (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.^[2]

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.^[3] 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.^[4]

SMO can function as an oncogene. Activating SMO mutations can lead to unregulated activation of the hedgehog pathway and cancer.^[5]

Overview of signal transduction pathways involved in apoptosis.

Agonists

• Smoothened agonist (SAG)
• Purmorphamine

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

See also

• Frizzled

References

1. Ruiz-Gómez A, Molnar C, Holguín H, Mayor F, de Celis JF (Apr 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.
2. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (Aug 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.
3. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (Oct 2005). "Vertebrate Smoothened functions at the primary cilium". Nature 437 (7061): 1018–21. doi:10.1038/nature04117. PMID 16136078.
4. Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy PA (Nov 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.
5. 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 (Jan 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 (Nov 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 (Nov 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 (Jan 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 (Sep 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 (Nov 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 (Nov 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 (Aug 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 (Dec 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 (Jun 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 (Aug 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 (Aug 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 (Sep 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 (Dec 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 (Jun 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 (Dec 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.

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)