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.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000128602 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001761 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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 (BBA) - Biomembranes. 1768 (4): 901–12. doi:10.1016/j.bbamem.2006.09.020. hdl:10261/4737. PMID 17094938.
- ^ Wang C, Wu H, Evron T, Vardy E, Han GW, Huang XP, Hufeisen SJ, Mangano TJ, Urban DJ, Katritch V, Cherezov V, Caron MG, Roth BL, Stevens RC (July 2014). "Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs". Nature Communications. 5: 4355. Bibcode:2014NatCo...5.4355W. doi:10.1038/ncomms5355. PMC 4198951. PMID 25008467.
- ^ 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. Bibcode:2000Natur.406.1005T. doi:10.1038/35023008. PMID 10984056. S2CID 4313790.
- ^ "Vismodegib, First Hedgehog Inhibitor, Approved for BCC Patients". OncLive. Retrieved 2017-05-26.
- ^ Kong JH, Siebold C, Rohatgi R (May 2019). "Biochemical mechanisms of vertebrate hedgehog signaling". Development. 146 (10): dev166892. doi:10.1242/dev.166892. PMC 6550017. PMID 31092502.
- ^ Jeng KS, Chang CF, Lin SS (January 2020). "Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments". Int J Mol Sci. 21 (3): 758. doi:10.3390/ijms21030758. PMC 7037908. PMID 31979397.
- ^ Liu X, Ding C, Tan W, Zhang A (February 2020). "Medulloblastoma: Molecular understanding, treatment evolution, and new developments". Pharmacol. Ther. 210: 107516. doi:10.1016/j.pharmthera.2020.107516. PMID 32105673. S2CID 211557426.
- ^ Laliscia C, Baldaccini D, Antonuzzo A, Paiar F (2019). "Vismodegibfor the treatment of radiation-induced basal cell carcinoma - a case report and brief literature study". Contemp Oncol (Pozn). 23 (4): 251–253. doi:10.5114/wo.2019.91540. PMC 6978755. PMID 31992959.
- ^ Liao S, Floyd C, Verratti N, Leung L, Wu C (March 2020). "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. doi:10.1016/j.lfs.2020.117302. PMID 31953165.