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Gene Review

SMO  -  smoothened, frizzled class receptor

Homo sapiens

Synonyms: FZD11, Gx, Protein Gx, SMOH, Smoothened homolog
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Disease relevance of SMO


High impact information on SMO

  • Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH) [4].
  • De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets [4].
  • We report here the identification of activating somatic missense mutations in the SMO gene itself in sporadic BCCs from three patients [3].
  • These findings support the role of SMO as a signalling component of the SHH-receptor complex and provide direct evidence that mutated SMO can function as an oncogene in BCCs [3].
  • Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO [5].

Chemical compound and disease context of SMO

  • In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells [6].
  • The objective of this paper is to investigate the protein distribution of SHH and its receptor PTC, SMO and transcription factor GLI1 in various odontogenic tumors [7].
  • Interestingly, the deduced amino acid sequence of Gx alpha predicts that the Gx alpha protein may be refractory to modification by pertussis toxin since the cysteine residue in the fourth position from the C terminus of pertussis toxin-sensitive G alpha is replaced by isoleucine [8].

Biological context of SMO

  • Mutational analysis identified four BCCs with somatic missense mutations in SMOH affecting codon 535 (TGG==>TTG: Trp==>Leu) in three tumors and codon 199 (CGG==>TGG: Arg==>Trp) in one tumor [2].
  • We demonstrate that SMO agonist Ag-1.4 mediates activation of extracellular signal-regulated kinase (Erk) phosphorylation, which is abrogated by IFNalpha in sonic hedgehog responsive C3H10T1/2 cells [9].
  • Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis [10].
  • We determined the methylation status and screened the gene encoding the Hedgehog receptor-associated protein Smoothened (SMO) for putative mutations [11].
  • Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed [12].

Anatomical context of SMO


Associations of SMO with chemical compounds

  • Another transmembrane protein, smoothened (SMO), forms a complex with PTC and regulates this signaling pathway [17].
  • The data are consistent with a model that directly links inflammation and DNA damage through the production of H(2)O(2) by SMO/PAOh1 [18].
  • SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H(2)O(2) [18].
  • The present study has therefore examined the effects of a moderately rough (sand-blasted, acid-etched; SLA) Ti surface, a highly rough (plasma-sprayed; TPS) surface, and a smooth surface (SMO) on bone cells in vitro [16].
  • Postoperative analgesia, including non-steroidal anti-inflammatory drugs, was provided using either pethidine patient-controlled epidural analgesia (group PCEA) or subarachnoid morphine 200 microg, the latter supplemented as required with patient-controlled intravenous pethidine (group SMPCIA) or oral paracetamol and codeine (group SMO) [19].

Physical interactions of SMO

  • Patched (PTCH) combines with Smoothened (SMO) to form a receptor complex for SHH ligand [20].

Regulatory relationships of SMO

  • Two additional cell lines both having one methylated SMO allele and expressing mutant SMO did not express GLI3 [11].
  • It now appears that constitutive activation of Hedgehog signalling, by inactivating mutations in PTCH1 or activating mutations in the coreceptor SMOH, is required and possibly sufficient for basal cell carcinoma development and also contributes to the formation of a variety of other tumour types, including medulloblastoma and rhabdomyosarcoma [21].

Other interactions of SMO

  • Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer [22].
  • We noted that high levels of SHH appear almost regularly, especially in dermoids, usually accompanied by increased expression of SMO [23].
  • Our results suggest that expression of wild-type SMO is required for expression of GLI3 by a mechanism that is independent of conventional Hedgehog signalling [11].
  • SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation [24].
  • Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development [25].

Analytical, diagnostic and therapeutic context of SMO


  1. Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Kallassy, M., Toftgård, R., Ueda, M., Nakazawa, K., Vorechovský, I., Yamasaki, H., Nakazawa, H. Cancer Res. (1997) [Pubmed]
  2. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Reifenberger, J., Wolter, M., Weber, R.G., Megahed, M., Ruzicka, T., Lichter, P., Reifenberger, G. Cancer Res. (1998) [Pubmed]
  3. Activating Smoothened mutations in sporadic basal-cell carcinoma. Xie, J., Murone, M., Luoh, S.M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J.M., Lam, C.W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E.H., de Sauvage, F.J. Nature (1998) [Pubmed]
  4. Mutations in SUFU predispose to medulloblastoma. Taylor, M.D., Liu, L., Raffel, C., Hui, C.C., Mainprize, T.G., Zhang, X., Agatep, R., Chiappa, S., Gao, L., Lowrance, A., Hao, A., Goldstein, A.M., Stavrou, T., Scherer, S.W., Dura, W.T., Wainwright, B., Squire, J.A., Rutka, J.T., Hogg, D. Nat. Genet. (2002) [Pubmed]
  5. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Fukaya, M., Isohata, N., Ohta, H., Aoyagi, K., Ochiya, T., Saeki, N., Yanagihara, K., Nakanishi, Y., Taniguchi, H., Sakamoto, H., Shimoda, T., Nimura, Y., Yoshida, T., Sasaki, H. Gastroenterology (2006) [Pubmed]
  6. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Mimeault, M., Moore, E., Moniaux, N., Hénichart, J.P., Depreux, P., Lin, M.F., Batra, S.K. Int. J. Cancer (2006) [Pubmed]
  7. Epithelial expression of SHH signaling pathway in odontogenic tumors. Zhang, L., Chen, X.M., Sun, Z.J., Bian, Z., Fan, M.W., Chen, Z. Oral Oncol. (2006) [Pubmed]
  8. Sequence analysis of cDNA and genomic DNA for a putative pertussis toxin-insensitive guanine nucleotide-binding regulatory protein alpha subunit. Matsuoka, M., Itoh, H., Kozasa, T., Kaziro, Y. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  9. IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Li, C., Chi, S., He, N., Zhang, X., Guicherit, O., Wagner, R., Tyring, S., Xie, J. Oncogene (2004) [Pubmed]
  10. Activation of the hedgehog pathway in human hepatocellular carcinomas. Huang, S., He, J., Zhang, X., Bian, Y., Yang, L., Xie, G., Zhang, K., Tang, W., Stelter, A.A., Wang, Q., Zhang, H., Xie, J. Carcinogenesis (2006) [Pubmed]
  11. Functional Smoothened is required for expression of GLI3 in colorectal carcinoma cells. Zhu, Y., James, R.M., Peter, A., Lomas, C., Cheung, F., Harrison, D.J., Bader, S.A. Cancer Lett. (2004) [Pubmed]
  12. Congenital linear unilateral basal cell nevus: a case report with patched gene molecular studies. Brailey, L.L., Davis, T., Kolker, S.E., Murry, T.C., Thomas, D., Bale, A.E., Ruhoy, S.M. J. Cutan. Pathol. (2007) [Pubmed]
  13. Expression of Sonic hedgehog pathway genes is altered in colonic neoplasia. Oniscu, A., James, R.M., Morris, R.G., Bader, S., Malcomson, R.D., Harrison, D.J. J. Pathol. (2004) [Pubmed]
  14. The magnitude of hedgehog signaling activity defines skin tumor phenotype. Grachtchouk, V., Grachtchouk, M., Lowe, L., Johnson, T., Wei, L., Wang, A., de Sauvage, F., Dlugosz, A.A. EMBO J. (2003) [Pubmed]
  15. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Athar, M., Li, C., Tang, X., Chi, S., Zhang, X., Kim, A.L., Tyring, S.K., Kopelovich, L., Hebert, J., Epstein, E.H., Bickers, D.R., Xie, J. Cancer Res. (2004) [Pubmed]
  16. Roughness response genes in osteoblasts. Brett, P.M., Harle, J., Salih, V., Mihoc, R., Olsen, I., Jones, F.H., Tonetti, M. Bone (2004) [Pubmed]
  17. Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Tojo, M., Mori, T., Kiyosawa, H., Honma, Y., Tanno, Y., Kanazawa, K.Y., Yokoya, S., Kaneko, F., Wanaka, A. Pathol. Int. (1999) [Pubmed]
  18. Tumor Necrosis Factor-{alpha} Increases Reactive Oxygen Species by Inducing Spermine Oxidase in Human Lung Epithelial Cells: A Potential Mechanism for Inflammation-Induced Carcinogenesis. Babbar, N., Casero, R.A. Cancer Res. (2006) [Pubmed]
  19. Postoperative intraspinal opioid analgesia after caesarean section; a randomised comparison of subarachnoid morphine and epidural pethidine. Paech, M.J., Pavy, T.J., Orlikowski, C.E., Kuh, J., Yeo, S.T., Lim, K., Evans, S.F. International journal of obstetric anesthesia. (2000) [Pubmed]
  20. Inhibition of SHH signaling pathway: Molecular treatment strategy of odontogenic keratocyst. Zhang, L., Sun, Z.J., Zhao, Y.F., Bian, Z., Fan, M.W., Chen, Z. Med. Hypotheses (2006) [Pubmed]
  21. Hedgehog signalling in cancer. Toftgård, R. Cell. Mol. Life Sci. (2000) [Pubmed]
  22. Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review). Katoh, Y., Katoh, M. Int. J. Mol. Med. (2006) [Pubmed]
  23. Role of the hedgehog/patched signaling pathway in oncogenesis: a new polymorphism in the PTCH gene in ovarian fibroma. Levanat, S., Musani, V., Komar, A., Oreskovic, S. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  24. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Reifenberger, J., Wolter, M., Knobbe, C.B., Köhler, B., Schönicke, A., Scharwächter, C., Kumar, K., Blaschke, B., Ruzicka, T., Reifenberger, G. Br. J. Dermatol. (2005) [Pubmed]
  25. Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis. Kayed, H., Kleeff, J., Keleg, S., Büchler, M.W., Friess, H. J. Endocrinol. (2003) [Pubmed]
  26. Chromosomal localization of the human smoothened gene (SMOH) to 7q32. 3 by fluorescence in situ hybridization and radiation hybrid mapping. Sublett, J.E., Entrekin, R.E., Look, A.T., Reardon, D.A. Genomics (1998) [Pubmed]
  27. Medical staff's knowledge of pulse oximetry: a prospective survey conducted in a tertiary children's hospital. Teoh, L., Epstein, A., Williamson, B., Morton, J., Papadopoulos, D., Teng, A. Journal of paediatrics and child health. (2003) [Pubmed]
  28. A total heart/lung bypass simulator. Leonard, R.J. ASAIO transactions / American Society for Artificial Internal Organs. (1988) [Pubmed]
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