Biology:Smoothened

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor[1][2] 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.[3] It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).[4]

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.[5][6] Mutations in proteins that relay Hh signals between cells cause birth defects and cancer.[7] 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.[8][9] 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

Overview of signal transduction pathways involved in apoptosis.

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.[10] Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation.[11] 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.[12] 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.[13] In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched.[14]

After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown.[15] 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.[14]

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.[16][17] SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage.[18][19] 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.[14]

Endogenous activation

Sterol Binding Sites in Smo CRD and TMD

A leading hypothesis in the field is that Ptc regulates Smo by gating its access to cholesterol or a related sterol.[20] 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.[21][22] 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.[23] 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).[24][25][26]

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.[24][27]

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.[28] 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.[23] Additionally, Molecular Dynamics simulations suggest that vismodegib inhibits Smo through a conformational change that prevents cholesterol from binding.[29] 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

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.[12][30] 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.[12]

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.[31] 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.[14]

Agonists

Antagonists

See also

References

  1. ↑ "The cell biology of Smo signalling and its relationships with GPCRs". Biochimica et Biophysica Acta (BBA) - Biomembranes 1768 (4): 901–12. April 2007. doi:10.1016/j.bbamem.2006.09.020. PMID 17094938. 
  2. ↑ "Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs". Nature Communications 5: 4355. July 2014. doi:10.1038/ncomms5355. PMID 25008467. Bibcode: 2014NatCo...5.4355W. 
  3. ↑ "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine". Nature 406 (6799): 1005–9. August 2000. doi:10.1038/35023008. PMID 10984056. Bibcode: 2000Natur.406.1005T. 
  4. ↑ "Vismodegib, First Hedgehog Inhibitor, Approved for BCC Patients". OncLive. http://www.onclive.com/web-exclusives/vismodegib-first-hedgehog-inhibitor-approved-for-bcc-patients-. 
  5. ↑ "Biochemical mechanisms of vertebrate hedgehog signaling". Development 146 (10): dev166892. May 2019. doi:10.1242/dev.166892. PMID 31092502. 
  6. ↑ "Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments". Int J Mol Sci 21 (3): 758. January 2020. doi:10.3390/ijms21030758. PMID 31979397. 
  7. ↑ "Medulloblastoma: Molecular understanding, treatment evolution, and new developments". Pharmacol. Ther. 210: 107516. February 2020. doi:10.1016/j.pharmthera.2020.107516. PMID 32105673. 
  8. ↑ "Vismodegibfor the treatment of radiation-induced basal cell carcinoma - a case report and brief literature study". Contemp Oncol (Pozn) 23 (4): 251–253. 2019. doi:10.5114/wo.2019.91540. PMID 31992959. 
  9. ↑ "Analysis of vismodegib resistance in D473G and W535L mutants of SMO receptor and design of novel drug derivatives using molecular dynamics simulations". Life Sci. 244: 117302. March 2020. doi:10.1016/j.lfs.2020.117302. PMID 31953165. 
  10. ↑ "Patched1 regulates hedgehog signaling at the primary cilium". Science 317 (5836): 372–6. July 2007. doi:10.1126/science.1139740. PMID 17641202. Bibcode: 2007Sci...317..372R. 
  11. ↑ "Vertebrate Smoothened functions at the primary cilium". Nature 437 (7061): 1018–21. October 2005. doi:10.1038/nature04117. PMID 16136078. Bibcode: 2005Natur.437.1018C. 
  12. ↑ 12.0 12.1 12.2 "Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation". Proceedings of the National Academy of Sciences of the United States of America 106 (8): 2623–8. February 2009. doi:10.1073/pnas.0812110106. PMID 19196978. Bibcode: 2009PNAS..106.2623W. 
  13. ↑ "Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium". The Journal of Cell Biology 187 (3): 365–74. November 2009. doi:10.1083/jcb.200907126. PMID 19948480. 
  14. ↑ 14.0 14.1 14.2 14.3 "Smoothened Regulation: A Tale of Two Signals" (in en). Trends in Pharmacological Sciences 37 (1): 62–72. January 2016. doi:10.1016/j.tips.2015.09.001. PMID 26432668. 
  15. ↑ "Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process". Proceedings of the National Academy of Sciences of the United States of America 106 (9): 3196–201. March 2009. doi:10.1073/pnas.0813373106. PMID 19218434. Bibcode: 2009PNAS..106.3196R. 
  16. ↑ "The hedgehog signaling network". American Journal of Medical Genetics. Part A 123A (1): 5–28. November 2003. doi:10.1002/ajmg.a.20495. PMID 14556242. 
  17. ↑ "The role of kinases in the Hedgehog signalling pathway". EMBO Reports 9 (4): 330–6. April 2008. doi:10.1038/embor.2008.38. PMID 18379584. 
  18. ↑ "Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2". Molecular Cell 12 (5): 1261–74. November 2003. doi:10.1016/S1097-2765(03)00426-X. PMID 14636583. 
  19. ↑ "Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail". Genes & Development 17 (21): 2709–20. November 2003. doi:10.1101/gad.1136603. PMID 14597665. 
  20. ↑ "The interplay of Patched, Smoothened and cholesterol in Hedgehog signaling". Curr. Opin. Cell Biol. 61: 31–38. December 2019. doi:10.1016/j.ceb.2019.06.008. PMID 31369952. 
  21. ↑ "Smoothened stimulation by membrane sterols drives Hedgehog pathway activity". Nature 571 (7764): 284–288. July 2019. doi:10.1038/s41586-019-1355-4. PMID 31263273. 
  22. ↑ "Structures of vertebrate Patched and Smoothened reveal intimate links between cholesterol and Hedgehog signalling". Curr. Opin. Struct. Biol. 57: 204–214. August 2019. doi:10.1016/j.sbi.2019.05.015. PMID 31247512. 
  23. ↑ 23.0 23.1 "Cholesterol accessibility at the ciliary membrane controls hedgehog signaling". eLife 8. October 2019. doi:10.7554/eLife.50051. PMID 31657721. 
  24. ↑ 24.0 24.1 "Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling". eLife 5. October 2016. doi:10.7554/eLife.20304. PMID 27705744. 
  25. ↑ *"Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened". Structure 27 (3): 549–559.e2. March 2019. doi:10.1016/j.str.2018.11.003. PMID 30595453. 
  26. ↑ "Multiple ligand binding sites regulate the Hedgehog signal transducer Smoothened in vertebrates". Curr. Opin. Cell Biol. 51: 81–88. April 2018. doi:10.1016/j.ceb.2017.10.004. PMID 29268141. 
  27. ↑ "Signaling in the primary cilium through the lens of the Hedgehog pathway". Wiley Interdiscip Rev Dev Biol 9 (6): e377. February 2020. doi:10.1002/wdev.377. PMID 32084300. 
  28. ↑ *"Motional dynamics of single Patched1 molecules in cilia are controlled by Hedgehog and cholesterol". Proc. Natl. Acad. Sci. U.S.A. 116 (12): 5550–5557. March 2019. doi:10.1073/pnas.1816747116. PMID 30819883. Bibcode: 2019PNAS..116.5550W. 
  29. ↑ "Deciphering the Allosteric Effect of Antagonist Vismodegib on Smoothened Receptor Deactivation Using Metadynamics Simulation". Front Chem 7: 406. 2019. doi:10.3389/fchem.2019.00406. PMID 31214579. Bibcode: 2019FrCh....7..406Y. 
  30. ↑ "Activating Smoothened mutations in sporadic basal-cell carcinoma". Nature 391 (6662): 90–2. January 1998. doi:10.1038/34201. PMID 9422511. Bibcode: 1998Natur.391...90X. 
  31. ↑ "Reduced cholesterol levels impair Smoothened activation in Smith-Lemli-Opitz syndrome". Human Molecular Genetics 25 (4): 693–705. February 2016. doi:10.1093/hmg/ddv507. PMID 26685159. 
  32. ↑ Patidegib

Further reading

External links



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