Smoothened

Last updated
SMO
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SMO , FZD11, Gx, SMOH, smoothened, frizzled class receptor, CRJS, PHLS
External IDs OMIM: 601500 MGI: 108075 HomoloGene: 4115 GeneCards: SMO
Orthologs
SpeciesHumanMouse
Entrez

6608

319757

Ensembl

ENSG00000128602

ENSMUSG00000001761

UniProt

Q99835

P56726

RefSeq (mRNA)

NM_005631

NM_176996

RefSeq (protein)

NP_005622

NP_795970

Location (UCSC) Chr 7: 129.19 – 129.21 Mb Chr 6: 29.74 – 29.76 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
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. [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

Sterol Binding Sites in Smo CRD and TMD Smo SterolBindingSites.png
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. [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

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

Antagonists

See also

Related Research Articles

<span class="mw-page-title-main">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Most commonly, protein phosphorylation is catalyzed by protein kinases, ultimately resulting in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

<span class="mw-page-title-main">Cilium</span> Organelle found on eukaryotic cells

The cilium is a membrane-bound organelle found on most types of eukaryotic cell. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projection that extends from the surface of the much larger cell body. Eukaryotic flagella found on sperm cells and many protozoans have a similar structure to motile cilia that enables swimming through liquids; they are longer than cilia and have a different undulating motion.

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.

<span class="mw-page-title-main">GLI1</span> Protein-coding gene in humans

Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.

<span class="mw-page-title-main">Cyclopamine</span> Chemical compound

Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. It is a teratogenic component of corn lily, which when consumed during gestation has been demonstrated to induce birth defects, including the development of a single eye (cyclopia) in offspring. The molecule was named after this effect, which was originally observed by Idaho lamb farmers in 1957 after their herds gave birth to cycloptic lambs. It then took more than a decade to identify corn lily as the culprit. Later work suggested that differing rain patterns had changed grazing behaviours, which led to a greater quantity of corn lily to be ingested by pregnant sheep. Cyclopamine interrupts the sonic hedgehog signalling pathway, instrumental in early development, ultimately causing birth defects.

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<span class="mw-page-title-main">Frizzled</span> Family of G-protein coupled receptor proteins

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<span class="mw-page-title-main">Indian hedgehog (protein)</span> Protein-coding gene in the species Homo sapiens

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Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segmentation in the fly embryo, mutations in which may be embryonic lethal. Patched functions as the receptor for the Hedgehog protein and controls its spatial distribution, in part via endocytosis of bound Hedgehog protein, which is then targeted for lysosomal degradation.

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<span class="mw-page-title-main">Vismodegib</span> Chemical compound

Vismodegib, sold under the brand name Erivedge, is a medication used for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval. The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011. The drug was developed by the biotechnology/pharmaceutical company Genentech.

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References

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  36. ↑ Patidegib

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