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Mechanisms of Wnt signaling and control

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The Wnt signaling pathway is a highly conserved system that regulates complex biological processes across all metazoan species. At the cellular level, secreted Wnt proteins serve to break symmetry and provide cells with positional information that is critical to the patterning of the entire body plan. At the organismal level, Wnt signals are employed to orchestrate fundamental developmental processes, including the specification of the anterior–posterior body axis, induction of the primitive streak and ensuing gastrulation movements, and the generation of cell and tissue diversity. Wnt functions extend into adulthood where they regulate stem cell behavior, tissue homeostasis, and damage repair. Disruption of Wnt signaling activity during embryonic development or in adults results in a spectrum of abnormalities and diseases, including cancer. The molecular mechanisms that underlie the myriad of Wnt‐regulated biological effects have been the subject of intense research for over three decades. This review is intended to summarize our current understanding of how Wnt signals are generated and interpreted. This article is categorized under: Biological Mechanisms > Cell Signaling Developmental Biology > Stem Cell Biology and Regeneration
Wnt secretion. Wnt proteins are translated into the endoplasmic reticulum where they are acylated by Porcupine (PORCN). Wntless (Wls/Evi) escorts acylated Wnt to the cell surface where it may associate with the plasma membrane (PM‐associated Wnt) or with proteoglycans (PG‐associated Wnt). Carrier proteins, such as SWIM and AFM, facilitate solubility of cell free Wnt proteins. Wnt proteins can signal at greater distances via cell projections (also known as filopodia, cytonemes, and nanotubes) or by associating with exosomes or liposomes
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β‐catenin mediated Wnt signaling. In the absence of a Wnt ligand, β‐catenin is sequestered by the multiprotein “destruction complex,” where it is phosphorylated and ubiquitinated, and targeted for proteasomal degradation. In the nucleus, LEF/TCF (lymphoid‐enhancing factor/T‐cell factor) transcription factors are resident on Wnt responsive elements (WREs), and recruit corepressors, such as Groucho/TLE. Upon Wnt‐Fzd interaction, LRP oligomerizes with the receptor‐ligand complex, and the destruction complex is dissociated. This leads to an accumulation of β‐catenin in the cytosol, and eventual translocation to the nucleus, where it interacts directly with LEF/TCF transcription factors, and other transcriptional coactivators to initiate target gene expression
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Regulating extracellular Wnt activity. Wnt signaling activity is modulated by three main mechanisms: (a) enzymatic inactivation by NOTUM, which cleaves off the essential lipid moiety, or by TIKI, which removes a portion of the amino terminus, (b) sequestration of Wnt by proteins such as WIF, SFRP, and Cer, and (C) receptor modulation by DKK, which binds LRP and Kremen to prevent the formation of a Wnt‐FZD‐LRP5/6 receptor complex, and by the ubiquitin ligases ZNRF3 and RNF43, which act to down regulate cell surface expression of FZD. Binding of the secreted protein RSPO to LGR5 interferes with the ability of these ubiquitin ligases to target FZD protein for degradation, thereby increasing Wnt receptor availability on the cell surface
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Wnt receptors. Several cell surface proteins directly bind Wnt proteins, including Frizzled (FZD), LRP5 & 6 (fly homolog is Arrow), PTK7 (fly homolog is Otk), ROR1 & 2, and RYK (fly homolog is Drl). Abbreviations: aa = amino acids, CRD = cysteine‐rich domain, C = carboxy terminus, Ig = immunoglobulin domain, N = amino terminus, WIF = Wnt inhibitory factor
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