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      Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk


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          Wnt signaling plays a major role in regulating cell proliferation and differentiation. The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either through β-catenin in the canonical pathway or through a series of other proteins in the noncanonical pathway. Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body, establishing the complex interplay between Wnt signaling and other signaling pathways. This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes. Dysregulation of this system has been implicated in many diseases affecting a wide array of organ systems, including cancer and embryological defects, and can even cause embryonic lethality. The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments. However, both stimulatory and inhibitory treatments come with potential risks that need to be addressed. This review synthesized much of the current knowledge on the Wnt signaling pathway, beginning with the history of Wnt signaling. It thoroughly described the different variants of Wnt signaling, including canonical, noncanonical Wnt/PCP, and the noncanonical Wnt/Ca 2+ pathway. Further description involved each of its components and their involvement in other cellular processes. Finally, this review explained the various other pathways and processes that crosstalk with Wnt signaling.

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          Most cited references452

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          The protein kinase complement of the human genome.

          G. Manning (2002)
          We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
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            Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

            The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
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              Identification of c-MYC as a target of the APC pathway.

              The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                24 March 2023
                January 2024
                24 March 2023
                : 11
                : 1
                : 103-134
                [a ]Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
                [b ]Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
                [c ]Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
                [d ]Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
                [e ]Department of Interventional Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
                [f ]Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
                [g ]School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
                [h ]Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
                Author notes
                []Corresponding author. Molecular Oncology Laboratory. The University of Chicago Medical Center. 5841 South Maryland Avenue, MC3079, Chicago, IL 60637, USA. Fax: +1 (773) 834 4598. tche@ 123456uchicago.edu lshi@ 123456bsd.uchicago.edu

                These authors contributed equally to the work.

                © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 3 August 2022
                : 1 November 2022
                : 29 January 2023
                Review Article

                β-catenin,canonical wnt,noncanonical wnt,signal transduction,signaling crosstalk


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