Cellular localization plays an essential role in the function of SMO, which anchors to the cell membrane as a 7-pass transmembrane protein. Stimulation of the patched 12-pass transmembrane receptor by the sonic hedgehog ligand leads to translocation of SMO to the primary cilium in vertebrates in a process that involves the exit of patched from the primary cilium, where it normally localizes in its unstimulated state.[5] Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation.[6] Conversely, SMO can become constitutively localized to the primary cilium and potentially activate pathway signaling constitutively as a result of a tryptophan to leucine mutation in the aforementioned domain.[7] SMO has been shown to move during patched stimulation from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway along the membrane, as opposed to via directed transport by vesicles. The cAMP-PKA pathway is known to promote the lateral movement of SMO and hedgehog signal transduction in general.[8] In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched.[9]
After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown.[10] There is evidence for the existence of an unidentified endogenous ligand that binds SMO and activates it. It is believed that mutations in SMO can mimic the ligand-induced conformation of SMO and activate constitutive signal transduction.[9]
SMO plays a key role in transcriptional repression and activation by the zinc-finger transcription factor Cubitus interruptus (Ci; known as Gli in vertebrates). When the hedgehog pathway is inactive, a complex of Fused (Fu), Supressor of Fused (Sufu), and the kinesin motor protein Costal-2 (Cos2) tether Ci to microtubules. In this complex, Cos2 promotes proteolytic cleavage of Ci by activating hyperphosphorylation of Ci and subsequent recruitment of ubiquitin ligase; the cleaved Ci goes on to act as a repressor of hedgehog-activated transcription. However, when hedgehog signaling is active, Ci remains intact and acts as a transcriptional activator of the same genes that its cleaved form suppresses.[11][12] SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage.[13][14] Additionally, it is known that vertebrate SMO contributes to the activation of Gli as a transcription factor via association with ciliary structures such as Evc2, but these mechanisms are not fully understood.[9]
SMO can function as an oncogene. Activating SMO mutations can lead to unregulated activation of the hedgehog pathway and serve as driving mutations for cancers such as medulloblastoma, basal-cell carcinoma, pancreatic cancer, and prostate cancer.[7][15] As such, SMO is an attractive cancer drug target, along with the many hedgehog pathway agonists and antagonists that are known to directly target SMO.[7]
Cholesterol is known to be crucial in regulating the overall hedgehog pathway, and congenital mutations in cholesterol synthesis pathways can inactivate SMO specifically, leading to developmental disorders.[16] For example, oxysterol 20(S)-OHC is known to activate vertebrate SMO by binding the cysteine rich domain near its extracellular amino-terminal region. In the context of cancer, 20(S)-OHC is the target of a proposed anti-cancer oxysterol binding inhibitor.[9]
Vismodegib (Erivedge), a smoothened receptor inhibitor for the treatment of basal-cell carcinoma, being investigated for the treatment of other types of cancer
↑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. PMID17094938.
↑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. PMID10984056.
↑Cohen MM (November 2003). "The hedgehog signaling network". American Journal of Medical Genetics. Part A. 123A (1): 5–28. doi:10.1002/ajmg.a.20495. PMID14556242.
↑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. PMID14636583.
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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. PMID9422511.
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. PMID9581815.
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. PMID9628830.
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. PMID9764827.
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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. PMID11042037.
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. PMID11748145.
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