The β-Catenin Destruction Complex
TL;DR: The molecular mechanisms of destruction complex function are reviewed and several potential roles of APC in β-catenin destruction are discussed, particularly the role ofAPC.
Abstract: The Wnt/β-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator β-catenin is degraded by a multiprotein “destruction complex” that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase β-TrCP. The complex generates a β-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the β-catenin amino terminus, a process that requires scaffolding of the kinases and β-catenin by Axin. Ubiquitinated β-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in β-catenin destruction.
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TL;DR: An overview of regulatory mechanisms and important developmental processes controlled by TAZ and YAP is provided and it is outlined that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors.
Abstract: Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
539 citations
Cites background from "The β-Catenin Destruction Complex"
...GSK3β associates with Axin and APC to make up a complex that targets the transcriptional regulator β-catenin for degradation (Stamos and Weis, 2013)....
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TL;DR: The current knowledge of Frizzled and LRP5/6 is reviewed, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of β-catenin phosphorylation and ensuing β- catenin stabilization.
Abstract: Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic β-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of β-catenin phosphorylation and ensuing β-catenin stabilization.
477 citations
TL;DR: An overview of Wnt-β-catenin signaling highlighting its key functions during development and adult tissue homeostasis is provided.
Abstract: The Wnt-β-catenin signaling pathway is an evolutionarily conserved cell-cell communication system that is important for stem cell renewal, cell proliferation and cell differentiation both during embryogenesis and during adult tissue homeostasis. Genetic or epigenetic events leading to hypo- or hyper-activation of the Wnt-β-catenin signaling cascade have also been associated with human diseases such as cancer. Understanding how this pathway functions is thus integral for developing therapies to treat diseases or for regenerative medicine approaches. Here, and in the accompanying poster, we provide an overview of Wnt-β-catenin signaling and briefly highlight its key functions during development and adult tissue homeostasis.
467 citations
TL;DR: The role of β-catenin in cancer initiation, progression, dormancy, immunity and cancer stem cell maintenance is focused on, and the recent progress in the development of agents for the pharmacological modulation ofβ-Catenin activity in cancer therapy is summarized.
Abstract: // Shuang Shang 1,* , Fang Hua 1,* and Zhuo-Wei Hu 1 1 Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China * These authors have contributed equally to this work Correspondence to: Zhuo-Wei Hu, email: // Keywords : Wnt signaling, protein stability, subcellular localization, transcriptional regulation, cancer therapy Received : December 20, 2016 Accepted : February 15, 2017 Published : February 25, 2017 Abstract Wnt/β-catenin signaling is an evolutionarily conserved and versatile pathway that is known to be involved in embryonic development, tissue homeostasis and a wide variety of human diseases. Aberrant activation of this pathway gives rise to the accumulation of β-catenin in the nucleus and promotes the transcription of many oncogenes such as c-Myc and CyclinD-1 . As a result, it contributes to carcinogenesis and tumor progression of several cancers, including colon cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer and ovarian cancer. β-Catenin is a pivotal component of the Wnt signaling pathway and it is tightly regulated at three hierarchical levels: protein stability, subcellular localization and transcriptional activity. Uncovering the regulatory mechanisms of β-catenin will provide new insights into the pathogenesis of cancer and other diseases, as well as new therapeutic strategies against these diseases. In this review we dissect the concrete regulatory mechanisms of β-catenin from three aspects mentioned above. Then we focus on the role of β-catenin in cancer initiation, progression, dormancy, immunity and cancer stem cell maintenance. At last, we summarize the recent progress in the development of agents for the pharmacological modulation of β-catenin activity in cancer therapy.
426 citations
TL;DR: The stage is now set to decode the methylproteome and define its functions in health and disease with recent advances in proteomic techniques.
Abstract: Lys and Arg methylation on non-histone proteins regulates various signalling pathways, and its crosstalk with other post-translational modifications and with histone methylation affects cellular processes such as transcription and DNA damage repair. Advances in proteomics now allow us to decode the methylproteome and elucidate its functions.
382 citations
References
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TL;DR: It is shown that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3, and it is demonstrated that PKB is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC).
Abstract: Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
5,158 citations
"The β-Catenin Destruction Complex" refers background in this paper
...When phosphorylated by other serine/threonine kinases, including Akt and p70S6K (Cross et al. 1995; Peyrollier et al. 2000), this phosphopeptide inhibits GSK-3 activity....
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TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
5,042 citations
TL;DR: Results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β- catenin.
Abstract: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.
3,859 citations
TL;DR: Constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium.
Abstract: The adenomatous polyposis coli (APC) tumor suppressor protein binds to beta-catenin, a protein recently shown to interact with Tcf and Lef transcription factors. The gene encoding hTcf-4, a Tcf family member that is expressed in colonic epithelium, was cloned and characterized. hTcf-4 transactivates transcription only when associated with beta-catenin. Nuclei of APC-/- colon carcinoma cells were found to contain a stable beta-catenin-hTcf-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta-catenin from hTcf-4 and abrogated the transcriptional transactivation. Constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium.
3,357 citations
TL;DR: β-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals from cell-adhesion components or wnt protein to the nucleus.
Abstract: The cytoplasmic proteins beta-catenin of vertebrates and armadillo of Drosophila have two functions: they link the cadherin cell-adhesion molecules to the cytoskeleton, and they participate in the wnt/wingless signal pathway. Here we show, in a yeast two-hybrid screen, that the architectural transcription factor LEF-1 (for lymphoid enhancer-binding factor) interacts with beta-catenin. In mammalian cells, coexpressed LEF-1 and beta-catenin form a complex that is localized to the nucleus and can be detected by immunoprecipitation. Moreover, LEF-1 and beta-catenin form a ternary complex with DNA that splays an altered DNA bend. Microinjection of LEF-1 into XenoPus embryos induces axis duplication, which is augmented by interaction with beta-catenin. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus.
2,761 citations