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      Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

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          Abstract

          Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.

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          Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

          Shih-Min A Huang, Yuji M. Mishina, Shanming Liu … (2009)
          The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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            A new member of the frizzled family from Drosophila functions as a Wingless receptor.

            P Bhanot, M. Brink, C Samos … (1996)
            Receptors for Wingless and other signalling molecules of the Wnt gene family have yet to be identified. We show here that cultured Drosophila cells transfected with a novel member of the frizzled gene family in Drosophila, Dfz2, respond to added Wingless protein by elevating the level of the Armadillo protein. Moreover, Wingless binds to Drosophila or human cells expressing Dfz2. These data demonstrate that Dfz2 functions as a Wingless receptor, and they imply, in general, that Frizzled proteins are receptors for the Wnt signalling molecules.
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              Genome-wide CRISPR screens reveal a Wnt–FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors

              Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar … (2016)
              A genome-wide CRISPR screen reveals that FZD5, but none of the other nine Frizzled receptors encoded in the human genome, is a therapeutic vulnerability of pancreatic and colorectal tumors bearing RNF43 mutations.
              Article 0 comments Cited 139 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 22 May 2018
                Publication date Collection: May 2018
                Volume: 19
                Issue: 5
                Electronic Location Identifier: 1543
                Affiliations
                [1 ]Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Research Centre, Shenzhen University School of Medicine, Shenzhen 518060, China; 2160220126@ 123456email.szu.edu.cn
                [2 ]Zhejiang Key Laboratory of Gastro-Intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; chenzhe@ 123456zju.edu.cn
                Author notes
                [* ]Correspondence: gracelfu@ 123456szu.edu.cn ; Tel.: +86-755-8667-1992
                Author information
                https://orcid.org/0000-0003-2643-6278
                Article
                Publisher ID: ijms-19-01543
                DOI: 10.3390/ijms19051543
                PMC ID: 5983605
                PubMed ID: 29789460
                SO-VID: 552bc83d-a9e6-436a-a21f-91ffa803371d
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 March 2018
                Date accepted : 19 May 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: frizzled receptors,wnt signaling pathway,cancer therapy,antibody,small molecule inhibitor
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: frizzled receptors, wnt signaling pathway, cancer therapy, antibody, small molecule inhibitor

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