Relevant bibliographies by topics / Smoothened signaling pathway

Academic literature on the topic 'Smoothened signaling pathway'

Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Smoothened signaling pathway"

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Kim, June Myoung, Hyeseung Han, Minjin Bahn, Yeokyu Hur, Chang-Yeol Yeo, and Dae-Won Kim. "Secreted tyrosine kinase Vlk negatively regulates Hedgehog signaling by inducing lysosomal degradation of Smoothened." Biochemical Journal 477, no. 1 (January 8, 2020): 121–36. http://dx.doi.org/10.1042/bcj20190784.

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Vlk is a secreted tyrosine kinase that plays crucial roles during vertebrate embryonic development including skeletal formation. Genetic studies suggest that Vlk can modulate the Hedgehog signaling pathway during skeletal development. Despite its potential roles as an extracellular regulator of signaling pathways, little is known regarding the molecular functions of Vlk. Here we show that Vlk can negatively regulate the Hedgehog signaling pathway. We found that Vlk can induce lysosomal degradation of Smoothened, a crucial transmembrane signal transducer of the Hedgehog pathway, through the interaction with the extracellular domain of Smoothened (Smo-ECD). In addition, we observed that Vlk can attenuate Hedgehog signaling-induced ciliary localization of Smoothened. Furthermore, Vlk-mediated suppression of Hedgehog signaling can be diminished by tyrosine-to-phenylalanine substitutions in Smo-ECD. Taken together, these results suggest that Vlk may function as a signaling regulator in extracellular space to modulate the Hedgehog pathway.
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Faria, Alessandra V. de S., Adamu Ishaku Akyala, Kaushal Parikh, Lois W. Brüggemann, C. Arnold Spek, Wanlu Cao, Marco J. Bruno, Maarten F. Bijlsma, Gwenny M. Fuhler, and Maikel P. Peppelenbosch. "Smoothened-dependent and -independent pathways in mammalian noncanonical Hedgehog signaling." Journal of Biological Chemistry 294, no. 25 (April 16, 2019): 9787–98. http://dx.doi.org/10.1074/jbc.ra119.007956.

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Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoothened. However, Smoothened inhibitors have yielded only partial success in combating Hedgehog signal transduction–dependent cancer, suggesting that noncanonical Smoothened-independent pathways also are clinically relevant. Moreover, several Smoothened-dependent effects (e.g. neurite projection) do not require transcriptional activation, further suggesting biological importance of noncanonical Smoothened-dependent pathways. We comprehensively characterized the cellular kinome in Hedgehog-challenged murine WT and Smoothened−/− fibroblasts as well as Smoothened agonist–stimulated cells. A peptide assay–based kinome analysis (in which cell lysates are used to phosphorylate specific kinase substrates), along with endocytosis, Lucifer Yellow–based, and immunoblotting assays, identified an elaborate signaling network of both Smoothened-dependent and -independent pathways that mediates actin reorganization through Src-like kinases, activates various proinflammatory signaling cascades, and concomitantly stimulates Wnt and Notch signaling while suppressing bone morphogenetic protein (BMP) signaling. The contribution of noncanonical Smoothened-independent signaling to the overall effects of Hedgehog on cellular physiology appears to be much larger than previously envisioned and may explain the transcriptionally independent effects of Hedgehog signaling on cytoskeleton. The observation that Patched-dependent, Smoothened-independent, noncanonical Hedgehog signaling increases Wnt/Notch signaling provides a possible explanation for the failure of Smoothened antagonists in combating Hedgehog-dependent but Smoothened inhibitor–resistant cancer. Our findings suggest that inhibiting Hedgehog–Patched interaction could result in more effective therapies as compared with conventional Smoothened-directed therapies.
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Jeng, Kuo-Shyang, I.-Shyan Sheen, Chuen-Miin Leu, Ping-Hui Tseng, and Chiung-Fang Chang. "The Role of Smoothened in Cancer." International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6863. http://dx.doi.org/10.3390/ijms21186863.

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Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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Khaliullina, Helena, Mesut Bilgin, Julio L. Sampaio, Andrej Shevchenko, and Suzanne Eaton. "Endocannabinoids are conserved inhibitors of the Hedgehog pathway." Proceedings of the National Academy of Sciences 112, no. 11 (March 2, 2015): 3415–20. http://dx.doi.org/10.1073/pnas.1416463112.

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Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.
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Meloni, Alison R., Gregory B. Fralish, Patrick Kelly, Ali Salahpour, James K. Chen, Robert J. Wechsler-Reya, Robert J. Lefkowitz, and Marc G. Caron. "Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2." Molecular and Cellular Biology 26, no. 20 (August 14, 2006): 7550–60. http://dx.doi.org/10.1128/mcb.00546-06.

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ABSTRACT Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many “conventional” 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and β-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by β-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between β-arrestin 2 and Smoothened.
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Fan, Junwan, Zichen Zhao, Ru Liu, Haowen Li, Wenyan He, Jianping Wu, Yongjun Wang, and Wei Chen. "A Potent Antagonist of Smoothened in Hedgehog Signaling for Epilepsy." International Journal of Molecular Sciences 23, no. 23 (November 22, 2022): 14505. http://dx.doi.org/10.3390/ijms232314505.

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Epilepsy is one of the common encephalopathies caused by sudden abnormal discharges of neurons in the brain. About 30% of patients with epilepsy are insensitive and refractory to existing antiseizure medications. The sonic hedgehog signaling pathway is essential to the development and homeostasis of brain. Aberrant sonic hedgehog signaling is increased in refractory epileptic lesions and may involve the etiology of epilepsy. Thus, new inhibitors of Smoothened, a key signal transducer of this signaling pathway are urgently need for refractory epilepsy. We have established a high-throughput screening platform and discovered several active small molecules targeting Smoothened including TT22. Here we show that the novel Smoothened inhibitor TT22 could block the translocation of βarrestin2-GFP to Smoothened, reduce the accumulation of Smoothened on primary cilia, displace Bodipy-cyclopamine binding to Smoothened, and inhibit the expression of downstream Gli transcription factor. Moreover, TT22 inhibits the abnormal seizure-like activity in neurons. Furthermore, we demonstrated that FDA-approved Smoothened inhibitor GDC-0449 and LDE-225 are able to inhibit abnormal seizure-like activity in neurons. Thus, our study suggests that targeting the sonic hedgehog signaling with new small-molecule Smoothened inhibitors might provide a potential new therapeutic avenue for refractory epilepsy.
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Gonnissen, Annelies, Sofie Isebaert, and Karin Haustermans. "Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened." Oncotarget 6, no. 16 (May 22, 2015): 13899–913. http://dx.doi.org/10.18632/oncotarget.4224.

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Pietrobono, Silvia, and Barbara Stecca. "Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors." Cells 7, no. 12 (December 14, 2018): 272. http://dx.doi.org/10.3390/cells7120272.

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Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.
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Martorana, Margherita. "A formalization of one of the main claims of “Sonic hedgehog signaling in astrocytes” by Hill et al. 20211." Data Science 5, no. 1 (March 22, 2022): 35–37. http://dx.doi.org/10.3233/ds-210043.

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Hill et al. claimed in previous work that sonic hedgehog signalling pathway is an essential regulator of astrocytes development. We present here a formalization of that claim, stating that all things of class “smoothened signaling pathway” that are in the context of a thing of class “human” mostly have a relation of type “affects” to a thing of class “astrocyte development” in the same context.
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Shyamala, Baragur V., and Krishna Moorthi Bhat. "A positive role for Patched-Smoothened signaling in promoting cell proliferation during normal head development in Drosophila." Development 129, no. 8 (April 15, 2002): 1839–47. http://dx.doi.org/10.1242/dev.129.8.1839.

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The transmembrane receptor Patched regulates several developmental processes in both invertebrates and vertebrates. In vertebrates, Patched also acts as a tumor suppressor. The Patched pathway normally operates by negatively regulating Smoothened, a G-protein-coupled receptor; binding of Hedgehog ligand to Patched relieves this negative interaction and allows signaling by Smoothened. We show that Ptc regulates Drosophila head development by promoting cell proliferation in the eye-antennal disc. During head morphogenesis, Patched positively interacts with Smoothened, which leads to the activation of Activin type I receptor Baboon and stimulation of cell proliferation in the eye-antennal disc. Thus, loss of Ptc or Smoothened activity affects cell proliferation in the eye-antennal disc and results in adult head capsule defects. Similarly, reducing the dose of smoothened in a patched background enhances the head defects. Consistent with these results, gain-of-function Hedgehog interferes with the activation of Baboon by Patched and Smoothened, leading to a similar head capsule defect. Expression of an activated form of Baboon in the patched domain in a patched mutant background completely rescues the head defects. These results provide insight into head morphogenesis, a process we know very little about, and reveal an unexpected non-canonical positive signaling pathway in which Patched and Smoothened function to promote cell proliferation as opposed to repressing it.
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Dissertations / Theses on the topic "Smoothened signaling pathway"

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Nedelcu, Daniel. "Smoothened regulation in the Hedgehog signaling pathway." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11080.

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Hedgehog signaling is a pathway essential in embryonic development, adult stem cell maintenance, and is implicated in the formation and progression of cancer. Signaling in this pathway is triggered when the secreted protein Hedgehog binds to its membrane receptor, Patched. Patched normally inhibits the seven-spanner transmembrane protein Smoothened (Smo). Binding of Hedgehog inhibits Patched resulting in Smo derepression. Active Smo then triggers the activation of the cytoplasmic steps of the signaling pathway.
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Bruzzone, Lucía. "A crosstalk between the RNA binding protein Smaug and the Hedgehog pathway links cell signaling to mRNA regulation in drosophila." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/BRUZZONE_Lucia_1_va_20180319.pdf.

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La régulation post-transcriptionnelle de l'expression génique joue un rôle essentiel dans divers processus cellulaires pendant le développement. Les protéines de liaison à l'ARN (RBP) sont des médiateurs fondamentaux des régulations post-transcriptionnelles qui contrôlent l'expression de l'ARNm en reconnaissant des séquences spécifiques dans les transcrits cibles. Smaug est une protéine de liaison à l'ARN conservée de la levure jusqu’à l’homme qui est essentielle pendant l'embryogenèse précoce de la drosophile. Smaug reconnaît et lie des éléments de reconnaissance de Smaug (SRE) dans ses ARNm cibles et recrute des facteurs supplémentaires, via des interactions protéine-protéine, qui régulent l'ARNm lié. Un concept qui émerge est celui des voies de signalisation pouvant moduler l'activité des RBP par des modifications post-traductionnelles, en ajoutant ainsi une couche supplémentaire dans le contrôle de l'expression des gènes.Au cours de mon travail de thèse, j'ai cherché à mettre en évidence que la voie de signalisation Hedgehog régule Smaug en favorisant sa phosphorylation. Mon travail montre que la signalisation HH diminue les niveaux de protéines Smaug affectant sa capacité à réprimer la traduction de l'ARNm. Cet effet négatif semble dépendre de l'interaction entre Smaug et le transducteur de signal HH, Smoothened. De plus, Smaug est constitutivement phosphorylée dans son domaine de liaison à l'ARN, ce qui semble être nécessaire pour la formation des foci cytoplasmiques de Smaug
Post-transcriptional regulation of gene expression plays a critical role in a variety of cellular processes during development. RNA binding proteins are fundamental mediators of post-transcriptional regulations that control mRNA expression by recognizing specific cis acting elements within the target transcripts. Smaug is a highly conserved sequence specific RNA-binding protein that is essential during Drosophila early embryogenesis. Smaug binds Smaug Recognition Elements (SRE) in the target mRNA and recruits additional factors, via protein-protein interactions, that regulate the bound mRNA. An emergent concept that signaling pathways can modulate RBP activity by post-translation modifications adds a new layer in the control of gene expression. During my thesis work, I sought to understand how the Hedgehog pathway regulates Smaug by promoting its phosphorylation. My work shows that HH signaling downregulates Smaug protein levels affecting its ability to repress mRNA translation. This negative effect seems to be dependent on the interaction between Smaug and the HH signal transducer Smoothened. Moreover, Smaug is constitutively phosphorylated in its RNA binding domain, which appears to be necessary for cytoplasmic Smaug foci formation
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Byrne, Eamon. "Molecular mechanisms of Hedgehog signal transduction by the G-protein coupled receptor smoothened." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:38abef20-ae98-4835-919c-73afc21a6252.

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The Hedgehog signalling pathway is an essential developmental pathway present in all bilaterians that is involved in embryogenesis, body patterning and stem cell homeostasis. Dysregulation of the Hh pathway leads to various kinds of cancer, such as basal cell carcinoma and medulloblastoma. Smoothened (SMO), a Frizzled-type G-protein coupled receptor (GPCR), is the essential transmembrane signal transducer within the Hh pathway, conveying the signal from the upstream transmembrane protein, Patched1 (Ptc1), to the downstream intracellular proteins. The mechanisms by which SMO transmits the Hh signal from the extracellular environment, through the plasma membrane and to the intracellular proteins are not known. In this thesis, I present my work into the structural and functional characterisation of the extracellular and transmembrane domains (TMD) of human SMO in order to better understand the molecular mechanisms of its signal transduction. The extracellular region of SMO contains a highly conserved cysteine-rich domain (CRD) and a linker domain (LD). I present the first crystal structure of the CRD, LD and TMD of SMO, which is also the first crystal structure of a GPCR with a large functional extracellular domain. This structure revealed a domain architecture for SMO that enables regulation of its transmembrane domain by its extracellular domains. It also revealed a cholesterol molecule bound to the CRD, which we subsequently determined to be a new endogenous small-molecule agonist for SMO. I present five further structures of SMO bound to different small molecule agonists and antagonists. Together, these structures demonstrate that the position of the CRD relative to the TMD reflects the activation state of SMO. We also generated nanobodies against the extracellular region of SMO in order to stabilise its conformation. These studies not only improve our understanding of the workings of a key transmembrane protein within a fundamental signalling pathway but will also aid efforts to develop better therapeutics for an important cancer target.
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Whalen, Daniel M. "Structural and functional studies of the hedgehog signalling pathway." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:ce0e765c-04f1-4a64-a67b-89204ecaa155.

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Hedgehog (Hh) morphogens play fundamental roles in development whilst dysregulation of Hh signalling leads to disease. Multiple receptors are involved in the modulation of Hh morphogens at the cell surface. Among these, the interactions of Hh ligands with glycosaminoglycan (GAG) (for example heparan or chondroitin sulphate) chains of proteoglycans in the extracellular matrix play a key role in shaping morphogen gradients and fulfil important functions in signal transduction. Several high resolution crystal structures of Sonic Hh (Shh)-GAG complexes have been determined. The interaction determinants, confirmed by binding studies and mutagenesis reveal a novel Hh site for GAG interactions, which appears to be common to all Hh proteins. This novel site is supported by a wealth of published functional data, and resides in a hot spot region previously found to be crucial for Hh receptor binding. Crystal packing analysis combined with analytical ultracentrifugation on Hh-GAG complexes suggest a potential mechanism for GAG-dependent multimerisation. A key step in the Hh pathway is the transduction of the Hh signal into the receiving cell. The Hh signal transducer, Smoothened, is a key target drug target in the pathway with several modulators in clinical trials, despite an absence of structural data. Smoothened is required to activate all levels of Hh signalling. Recent evidence points to the conserved N-terminal ectodomain (ECD) in regulating Smo activity, from vertebrates to invertebrates. Despite the central importance of the ECD, its precise function remains elusive. A crystal structure of the ECD at 2.2 Å resolution is reported here. Structural analysis and biophysical experiments are discussed with reference to the potential function of this intriguing domain.
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Tong, Chao. "Studies of Smoothened in Hedgehog Signaling Pathway." 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=232.

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Linder, Benedikt. "Interaction of the Hedgehog and vitamin D receptor signaling pathways in Patched associated cancers." Doctoral thesis, 2015. http://hdl.handle.net/11858/00-1735-0000-0022-5FDC-A.

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Conference papers on the topic "Smoothened signaling pathway"

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Karlou, Maria, Vassiliki Tzelepi, Sankar Maity, Nora M. Navone, Jun Yang, Jing‐Fang Lu, Anh Hoang, Christopher J. Logothetis, and Eleni Efstathiou. "Abstract C253: Effective inhibition of Hedgehog signaling pathway with small molecule Smoothened inhibitor GDC‐0449 in a bone producing prostate cancer xenograft." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-c253.

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Nasution, M. A. F., F. Stephanie, and U. S. F. Tambunan. "Pharmacophore-based virtual screening and molecular docking simulation of flavonoids as smoothened protein inhibitor of Hedgehog signaling pathways." In PROCEEDINGS OF THE 4TH INTERNATIONAL SYMPOSIUM ON CURRENT PROGRESS IN MATHEMATICS AND SCIENCES (ISCPMS2018). AIP Publishing, 2019. http://dx.doi.org/10.1063/1.5132487.

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