Smoothened
Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor[5][6] that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine.[7] It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).[8]
Smoothened (Smo) is a key transmembrane protein that is a key component of the hedgehog signaling pathway, a cell-cell communication system critical for embryonic development and adult tissue homeostasis.[9][10] Mutations in proteins that relay Hh signals between cells cause birth defects and cancer.[11] The protein that carries the Hh signal across the membrane is the oncoprotein and G-protein coupled receptor (GPCR) Smoothened (Smo). Smo is regulated by a separate transmembrane receptor for Hh ligands called Patched (Ptc). Ptc itself is a tumor suppressor that keeps the Hh pathway off by inhibiting Smo. The excessive Hh signaling that drives human skin and brain cancer is most frequently caused by inactivating mutations in Ptc or by gain of function mutations in Smo. While direct Smo agonists and antagonists, such as SAG and vismodegib, can bind to and activate or inhibit Smo, how Ptc inhibits Smo endogenously remains a mystery in the field.
Currently, Smo is targeted and inhibited directly by a small-molecule drug, vismodegib, for the treatment of advanced basal cell cancer, however widespread resistance to this drug has become a prevalent issue.[12][13] Finding another method to target Smo activity in Hh-driven cancers would provide valuable information for novel therapeutics. Identifying these Ptc responsive sites on Smo will help solve a long-standing mystery in Hh signaling and suggest new therapeutic strategies to block Smo activity in Hh-driven cancers.
Function
[edit]
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.[14] Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation.[15] 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.[16] 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.[17] In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched.[18]
After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown.[19] 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.[18]
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), Suppressor 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.[20][21] SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage.[22][23] 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.[18]
Endogenous activation
[edit]
A leading hypothesis in the field is that Ptc regulates Smo by gating its access to cholesterol or a related sterol.[24] It has been proposed that cholesterol activates Smo, and subsequently Hh signaling, by entering the active site through a hydrophobic “oxysterol tunnel,” which can adopt open or closed conformations to allow for activation or inactivation of Smo, respectively, due to allowed sterol binding.[25][26] Shh would work by inhibiting Ptc, which would increase accessible cholesterol concentrations and allow for the activation of Smo and transmission of the Hh signal.[27] A recent crystal structure has identified two sterol binding sites in Smo, but which site is endogenously regulated by Ptc remains to be determined. The potential sites of regulation include the extracellular cysteine-rich domain (CRD) of Smo, as well as a site deep within the transmembrane domain (TMD).[28][29][30]
Due to the abundance of cholesterol in the plasma membrane (up to 50 mole %), it has also been proposed that Ptc regulates the activity of Smo by controlling cholesterol accessibility specifically within the membrane of the primary cilia, which contains a less abundant, and therefore more readily regulated pool of accessible cholesterol.[28][31]
Typically, upon activation and release of inhibition by Ptc, Smo will relocate to the primary cilia and Ptc will diffuse out of the ciliary membrane.[32] Upon inactivation, Smo no longer becomes concentrated in the ciliary membrane, This hypothesis is supported by methods which can increase or deplete the accessible cholesterol pool, with a subsequent increase or decrease in Hh signaling. This accessible cholesterol pool has been shown to be distinct from the general plasma membrane cholesterol pool in being available for protein interaction and cell uptake. The ciliary membrane has also been shown to contain lower levels of accessible cholesterol due to sequestering of cholesterol by sphingomyelin. In addition to cholesterol’s role as a Hh pathway agonist, it has been shown that cholesterol levels within the ciliary membrane rapidly increase upon treatment with Shh only in the presence of Ptc, further suggesting Ptc regulation of accessible cholesterol as the mechanism behind Smo activation/inhibition.[27] Additionally, Molecular Dynamics simulations suggest that vismodegib inhibits Smo through a conformational change that prevents cholesterol from binding.[33] This suggests the hypothesis that Ptc functions by preventing Smo access to cholesterol, and upon Ptc inhibition by Shh, Smo gains access to cholesterol and is subsequently activated, transmitting the Hh signal.
Role in disease
[edit]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.[16][34] 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.[16]
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.[35] 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.[18]
Agonists
[edit]- Smoothened agonist (SAG)
- Purmorphamine
- Oxysterols including 20(S)-OHC and 20(S)-yne
Antagonists
[edit]- 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
- Patidegib[36]
- Glasdegib
- Jervine
See also
[edit]References
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Further reading
[edit]- 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. S2CID 15208834.
- 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. Bibcode:1996Natur.384..129S. doi:10.1038/384129a0. PMID 8906787. S2CID 4342540.
- 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. Bibcode:1998Natur.391...90X. doi:10.1038/34201. PMID 9422511. S2CID 205003240.
- 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. Bibcode:1998PNAS...9513630C. 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. doi:10.1242/dev.128.24.5099. 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. S2CID 3162414.
- 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. Bibcode:2002Natur.418..892T. doi:10.1038/nature00989. PMID 12192414. S2CID 4362029.
- 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. S2CID 21237084.
- 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. Bibcode:2004Sci...306.2257C. doi:10.1126/science.1104135. PMID 15618519. S2CID 12823611.
- 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. Bibcode:2016Natur.535..517B. doi:10.1038/nature18934. PMC 4970916. PMID 27437577.
External links
[edit]- "Frizzled Receptors: SMO". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-02-25. Retrieved 2007-10-25.
- SMO+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)