scholarly journals Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1

2020 ◽  
pp. jcs.251140
Author(s):  
Carlo D. Cristobal ◽  
Qi Ye ◽  
Juyeon Jo ◽  
Xiaoyun Ding ◽  
Chih-Yen Wang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Actin Polymerization ◽  
Critical Role ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Downstream Signaling ◽  
Receptor Complexes ◽  
Spinal Cord Dorsal ◽  
Canonical Wnt ◽  
Chick Spinal Cord

Wnt signaling plays a critical role in development across species and is dysregulated in a host of human diseases. A key step in signal transduction is the formation of Wnt receptor signalosomes, where a large number of components translocate to the membrane, cluster together, and amplify downstream signaling. However, the molecular processes that coordinate these events remain poorly defined. Here, we show that Daam2 regulates canonical Wnt signaling via the PIP2-PIP5K axis through its association with Rac1. Clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K, and PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner. Importantly, the localization of Daam2 complexes and Daam2-mediated canonical Wnt signaling is dependent upon actin polymerization. These studies highlight novel roles for Rac1 and the actin cytoskeleton in the regulation of canonical Wnt signaling and define Daam2 as a key scaffolding hub that coordinates membrane translocation and signalosome clustering. Key words: Daam2, Rac1, PIP5K, Wnt signalosome, chick spinal cord, dorsal patterning

scholarly journals Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

2020 ◽  
Author(s):  
Yueli Liu ◽  
Jiawen Wang ◽  
Corrigan Horton ◽  
Sol Katzman ◽  
Tao Cai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Target Genes ◽  
Critical Role ◽  
Gene Set Enrichment Analysis ◽  
Dependent Manner ◽  
Basal Cells ◽  
Canonical Wnt Signaling ◽  
Cell Functions ◽  
Canonical Wnt

AbstractBoth the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling down-regulated the expressions of a Wnt reporter as well as many Wnt target genes. Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and β–catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.

scholarly journals The Microphthalmia-Associated Transcription Factor Mitf Interacts with β-Catenin To Determine Target Gene Expression

2006 ◽  
Vol 26 (23) ◽  
pp. 8914-8927 ◽  
Author(s):  
Alexander Schepsky ◽  
Katja Bruser ◽  
Gunnar J. Gunnarsson ◽  
Jane Goodall ◽  
Jón H. Hallsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Feedback Mechanism ◽  
Canonical Wnt Signaling ◽  
Melanocyte Stem Cells ◽  
Canonical Wnt

ABSTRACT Commitment to the melanocyte lineage is characterized by the onset of expression of the microphthalmia-associated transcription factor (Mitf). This transcription factor plays a fundamental role in melanocyte development and maintenance and seems to be crucial for the survival of malignant melanocytes. Furthermore, Mitf has been shown to be involved in cell cycle regulation and to play important functions in self-renewal and maintenance of melanocyte stem cells. Although little is known about how Mitf regulates these various processes, one possibility is that Mitf interacts with other regulators. Here we show that Mitf can interact directly with β-catenin, the key mediator of the canonical Wnt signaling pathway. The Wnt signaling pathway plays a critical role in melanocyte development and is intimately involved in triggering melanocyte stem cell proliferation. Significantly, constitutive activation of this pathway is a feature of a number of cancers including malignant melanoma. Here we show that Mitf can redirect β-catenin transcriptional activity away from canonical Wnt signaling-regulated genes toward Mitf-specific target promoters to activate transcription. Thus, by a feedback mechanism, Mitf can diversify the output of canonical Wnt signaling to enhance the repertoire of genes regulated by β-catenin. Our results reveal a novel mechanism by which Wnt signaling and β-catenin activate gene expression, with significant implications for our understanding of both melanocyte development and melanoma.

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

2005 ◽  
Vol 333 (4) ◽  
pp. 1300-1308 ◽  
Author(s):  
Fumiko Yano ◽  
Fumitaka Kugimiya ◽  
Shinsuke Ohba ◽  
Toshiyuki Ikeda ◽  
Hirotaka Chikuda ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Chondrocyte Differentiation ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

scholarly journals Deregulation of the histone H3K9 di-methylation landscape suppresses canonical Wnt signaling in embryonal rhabdomyosarcoma

2020 ◽  
Author(s):  
Ananya Pal ◽  
Jia Yu Leung ◽  
Gareth Chin Khye Ang ◽  
Vinay Kumar Rao ◽  
Luca Pignata ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Myogenic Differentiation ◽  
Wnt Signaling Pathway ◽  
Embryonal Rhabdomyosarcoma ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Therapeutic Modalities ◽  
Canonical Wnt

AbstractThe Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the H3K9 lysine methyltransferase G9a suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of G9a expression or activity reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in vivo. Mechanistically, G9a impacted Sp1 and p300 enrichment at the DKK1 promoter in a methylation-dependent manner. The reduced tumor growth upon G9a deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability. Together, our study demonstrates that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1-β-catenin node holds promise for differentiation therapy.

scholarly journals Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development

Development ◽  
2020 ◽  
pp. dev.196360
Author(s):  
Yuanyuan Ma ◽  
Junjun Jing ◽  
Jifan Feng ◽  
Yuan Yuan ◽  
Quan Wen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Root Development ◽  
Critical Role ◽  
Canonical Wnt Signaling ◽  
Dental Tissue ◽  
Tooth Formation ◽  
Size And Shape ◽  
Dental Tissue Engineering ◽  
Canonical Wnt

The control of size and shape is an important part of regulatory process during organogenesis. Tooth formation is a highly complex process that fine-tunes the size and shape of the tooth, which are crucial for its physiological functions. Each tooth consists of a crown and one or more roots. Despite comprehensive knowledge of the mechanism that regulates early tooth crown development, we have limited understanding of the mechanism regulating root patterning and size during development. Here we show that Ror2 mediated non-canonical Wnt signaling in the dental mesenchyme plays a critical role in cell proliferation and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation. Importantly, activation of Cdc42 can restore cell proliferation and partially rescue the root development size defects in Ror2 mutant mice. Collectively, our findings provide novel insights into the function of Ror2-mediated non-canonical Wnt signaling in regulating tooth morphogenesis and suggest potential avenues for dental tissue engineering.

scholarly journals Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling

2013 ◽  
Vol 305 (3) ◽  
pp. G241-G249 ◽  
Author(s):  
Shuji Yamamoto ◽  
Hiroshi Nakase ◽  
Minoru Matsuura ◽  
Yusuke Honzawa ◽  
Kayoko Matsumura ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Binding Affinity ◽  
Target Genes ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Intestinal Epithelial ◽  
Canonical Wnt Signaling ◽  
Small Intestinal ◽  
Canonical Wnt

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.

scholarly journals Chlorogenic Acids Inhibit Adipogenesis: Implications of Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Mengting Liu ◽  
Jian Qin ◽  
Jing Cong ◽  
Yubin Yang
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Fatty Acid Synthase ◽  
Adipocyte Differentiation ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Canonical Wnt Signaling ◽  
Ppar Γ ◽  
Gsk 3Β ◽  
Canonical Wnt

In our previous in vitro study, we found that chlorogenic acid (CGA) inhibited adipocyte differentiation and triglyceride (TG) accumulation, but the underlying mechanism is still unclear. Accumulative genetic evidence supports that canonical Wnt signaling is a key modulator on adipogenesis. Methods. In this study, 3T3-L1 cells were induced adipogenic differentiation and then treated with CGA. We investigate the effect of CGA in inhibiting adipogenesis and evaluate its role in modulating Wnt10b (wingless integration1 10b), β-catenin, glycogen synthase kinase-3β (GSK-3β), and peroxisome proliferator-activated receptor γ (PPAR-γ) involved in the Wnt (wingless integration1)/β-catenin signaling pathway. Results. The result showed that after CGA treatment, lipid accumulation and TG level decreased significantly in 3T3-L1 cells, indicating that CGA could inhibit adipogenesis. In addition, CGA repressed the induction of adipocyte differentiation biomarkers as PPAR-γ, adipocyte protein 2 (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL), and the secretion of GSK-3β in a dose-dependent manner upregulated the expression of β-catenin and Wnt10b both in gene and protein levels. Moreover, CGA induced phosphorylation of GSK-3β and promoted the accumulation of free cytosolic β-catenin in 3T3-L1 adipocytes. Conclusion. Overall, these findings gave us the implications that CGA inhibits adipogenesis via the canonical Wnt signaling pathway.

scholarly journals Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling

2005 ◽  
Vol 97 (2) ◽  
pp. 144-151 ◽  
Author(s):  
Atsuhiko T. Naito ◽  
Hiroshi Akazawa ◽  
Hiroyuki Takano ◽  
Tohru Minamino ◽  
Toshio Nagai ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Critical Role ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Phosphatidylinositol 3
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