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Meta-analysis of the literature. Br J Cancer. J Oral Pathol Med. Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Prostaglandin E2 promotes colon cancer cell growth through a Gs-Axin- -catenin signaling axis.
Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer. Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. J Immunol. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch.
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A role for Wnt signalling in self-renewal of haematopoietic stem cells. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Launching the T-cell-lineage developmental programme. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. B-1 cells and B-1 cell precursors prompt different responses to Wnt signaling. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. Escors D. Tumour immunogenicity, antigen presentation, and immunological barriers in cancer immunotherapy.
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Dickkopf-related protein 1 Dkk1 regulates the accumulation and function of myeloid derived suppressor cells in cancer. Wnt5a skews dendritic cell differentiation to an unconventional phenotype with tolerogenic features. Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. Manicassamy S, Pulendran B. Dendritic cell control of tolerogenic responses. Immunol Rev. A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy.
The use of porcupine inhibitors to target Wnt-driven cancers. Bioorg Med Chem Lett. Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy. Br J Pharmacol. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. J Clin Oncol. A phase Ib dose escalation study of vantictumab VAN in combination with nab-paclitaxel Nab-P and gemcitabine G in patients with previously untreated stage IV pancreatic cancer.
A first-in-human phase I study of the anticancer stem cell agent Ipafricept OMPF28 , a decoy receptor for Wnt ligands, in patients with advanced solid tumors. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Sci Adv. Kim MK. Novel insight into the function of tankyrase. Oncol Lett. Tankyrases: structure, function and therapeutic implications in cancer. Curr Pharm Des. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies.
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Nature, : —7. Nat Cell Biol, 4 7 : E—3. Wnt signaling resources. All interactive pathways. What to expect from our Wnt pathway poster? The planar cell polarity pathway In the planar cell polarity pathway, Wnt signaling through Frizzled receptors mediates asymmetric cytoskeletal organization and the polarization of cells by inducing modifications to the actin cytoskeleton.
Antagonists of Wnt signaling Wnt antagonists can be divided into two functional classes: the secreted Frizzled related proteins sFRP class and the Dickkopf Dkk class 2. References 1. Current approaches to elucidate the mechanisms of catenin regulation include attempts to determine the structure of the degradation complex. Mutations in either of these genes result in wingless-like phenotypes in Drosophila , and both genes promote Wnt signaling in mammalian cell culture experiments The Wnt pathway has numerous transcriptional endpoints.
The large majority of these is cell type specific, i. This specificity is commonly seen in developmental signaling pathways, and reflects the fundamental mechanism of gene control by extracellular signals: the cell rather than the signal determines the nature of the response. But in addition to the cell type specific genes, Wnt signaling also controls genes that are more widely induced.
Given the diverse phenotypes produced by Wnt knock-outs in mice, it is not surprising that loss of Wnts in humans has dire consequences as well.
Recently, Tetra-amelia, a rare human genetic disorder characterized by absence of limbs, has been proposed to result from WNT3 loss of function mutations In adults, mis-regulation of the Wnt pathway also leads to a variety of abnormalities and disease.
An LRP mutation has been identified that causes increased bone density at defined locations such as the jaw and palate 33 , The mutation is a single amino-acid substitution that makes LRP5 insensitive to Dkk-mediated Wnt pathway inhibition, indicating that the phenotype results from over-active Wnt signaling in the bone In a different study, mutations in LRP5 were correlated with decreased bone mass In this case, frame shift and missense mutations were thought to create loss-of-function LRP5 mutations.
These data indicate that Wnt signaling mediated by LRP5 is required for maintenance of normal bone density. Mutations that promote constitutive activation of the Wnt signaling pathway lead to cancer. The best-known example is Familial Adenomatous Polyposis FAP , an autosomal, dominantly inherited disease in which patients display polyps in the colon and rectum. This disease is caused most frequently by truncations in APC 36 , 37 that promote aberrant activation of the Wnt pathway leading to adenomatous lesions due to increased cell proliferation.
Loss-of-function mutations in Axin have been found in hepatocellular carcinomas In the colon, loss of TCF4 or Dkk over-expression promotes loss of stem cells in the colon crypt, indicating that Wnt signaling is required for maintenance of the stem cell compartment 40 , 41 , Wnt signaling may therefore be a fundamental regulator of stem cell choices to proliferate or self-renew. Wnt proteins are lipid-modified and can act as stem cell growth factors.
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Science ; — Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell ; 12 — Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.
Mol Cell ; 7 —9. Genes Dev ; 16 — Cell ; — Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. Embo J ; 21 — The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Mutations affecting segment number and polarity in Drosophila. Nature ; — The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless.
Cell ; 50 — Dishevelled and armadillo act in the wingless signalling pathway in Drosophila. CAS Google Scholar. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties.
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Science ; Wnt proteins are lipid-modified and can act as stem cell growth factors. Structural basis of Wnt recognition by Frizzled. In vivo role of lipid adducts on Wingless. J Cell Sci ; Pt 10 — Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem J ; — Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci ; 25 — The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.
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Dev Cell ; 29 — Gpr regulates pulmonary vasculature development. Development ; — The apical and basolateral secretion of Wnt11 and Wnt3a in polarized epithelial cells is regulated by different mechanisms. J Cell Sci ; Pt 13 — Wntless functions in mature osteoblasts to regulate bone mass. Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis. Dev Biol ; — Dev Dyn ; — Drosophila Tcf and Groucho interact to repress Wingless signalling activity. BMC Cancer ; 9 J Cell Sci ; Pt 9 — EMBO J ; 26 — Cell ; 99 — Tetsu O, McCormick F.
Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Mol Cell Biol ; 22 — A transcriptional response to Wnt protein in human embryonic carcinoma cells. Dev Biol ; 2 Google Scholar. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol ; — Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1. PLoS One ; 4 :e Dev Cell ; 32 — The small molecule Wnt signaling modulator ICG improves contractile function in chronically infarcted rat myocardium.
PLoS One ; 8 :e J Biol Chem ; — Acetylation of beta-catenin by p regulates beta-catenin-Tcf4 interaction. Mol Cell Biol ; 24 — Glucose-induced beta-catenin acetylation enhances Wnt signaling in cancer.
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Cell Cycle ; 5 — Dev Cell ; 7 — R-Spondin family members regulate the Wnt pathway by a common mechanism. Mol Biol Cell ; 19 — Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. The R-spondin protein family. Genome Biol ; 13 Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development.
A new secreted protein that binds to Wnt proteins and inhibits their activities. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction.
Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol Cell Biol ; 28 — Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. Wise, a context-dependent activator and inhibitor of Wnt signalling. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res ; 19 — Wnt signaling in bone formation and its therapeutic potential for bone diseases.
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Oncogene ; 26 — Mol Cell ; 36 — Biochem Biophys Res Commun ; — Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene ; 20 — Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology ; 49 — Endocrinology ; — Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways.
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