Wnt/β-Catenin Signaling in Development and Disease

Clevers, Hans

doi:10.1016/j.cell.2006.10.018

Cited by 5,087 publications

(4,871 citation statements)

References 115 publications

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“…PAWS1‐dependent induction of Siamois expression was blocked by C‐cadherin (Fig 4D), suggesting that PAWS1‐mediated activation of Wnt signalling requires β‐catenin. Ubiquitin‐mediated degradation of β‐catenin is regulated through the destruction complex, in which CK1, GSK‐3 and Axin1 play key roles 25, 26, 27. Overexpression of Axin1 in animal caps completely blocked xPAWS1‐induced Siamois expression, while overexpression of GSK‐3 did so partially (Fig 4D).…”

Section: Resultsmentioning

confidence: 95%

PAWS 1 controls Wnt signalling through association with casein kinase 1α

Bozatzi

Dingwell

et al. 2018

EMBO Reports

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The BMP and Wnt signalling pathways determine axis specification during embryonic development. Our previous work has shown that PAWS1 (also known as FAM83G) interacts with SMAD1 and modulates BMP signalling. Here, surprisingly, we show that overexpression of PAWS1 in Xenopus embryos activates Wnt signalling and causes complete axis duplication. Consistent with these observations in Xenopus, Wnt signalling is diminished in U2OS osteosarcoma cells lacking PAWS1, while BMP signalling is unaffected. We show that PAWS1 interacts and co‐localises with the α isoform of casein kinase 1 (CK1), and that PAWS1 mutations incapable of binding CK1 fail both to activate Wnt signalling and to elicit axis duplication in Xenopus embryos.

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Section: Resultsmentioning

confidence: 95%

PAWS 1 controls Wnt signalling through association with casein kinase 1α

Bozatzi

Dingwell

et al. 2018

EMBO Reports

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“…Glycogen synthase kinase‐3β (GSK‐3β)‐dependent control of β‐catenin stability or degradation is thought to be the central regulatory mechanism of the canonical Wnt signaling pathway (Clevers, 2006). In the presence of Wnt, GSK‐3β is phosphorylated and inhibited, thus preventing targeting of β‐catenin for degradation.…”

Section: Resultsmentioning

confidence: 99%

“…Aberrant Wnt/β‐catenin signaling is known to play an important role in the initiation and maintenance of GC (Hidaka et al ., 2013; Ju et al ., 2014). While Wnt signaling is activated, β‐catenin is stabilized and accumulates in the cytoplasm and then migrates to the nucleus where it binds to the T‐cell factor/lymphoid enhancer‐binding factor (TCF/LEF) to promote transcription of various target genes, inducing those related to EMT (Clevers, 2006; Clevers and Nusse, 2012; Huang et al ., 2014). In the present study, we found that DDAH1 overexpression significantly decreased the level of β‐catenin, whereas its knockdown produced the opposite effect.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, a study has shown that DDAH1 can inhibit the renal fibrosis process via the Wnt/β‐catenin pathway (Liu et al ., 2016), a well‐established crucial signaling event associated with a number of human diseases (Miao et al ., 2013; Miki et al ., 2011; de Sousa et al ., 2011) including cancer (Ramachandran et al ., 2012). Wnt signaling regulates various functions of the cancer cell such as proliferation, cell fate decision, motility and invasion through activating β‐catenin (Clevers, 2006). A large body of evidences have suggested that the canonical Wnt/β‐catenin pathway plays an important role in inducing epithelial cancer cells to undergo epithelial–mesenchymal transition (EMT; Brabletz et al ., 2005; Taki et al ., 2003), which facilitates migration through the extracellular matrix and distant metastasis.…”

Section: Introductionmentioning

confidence: 99%

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DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

et al. 2017

Molecular Oncology

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Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the main enzyme that can degrade asymmetric dimethylarginine, an endogenous nitric oxide synthase (NOS) inhibitor. Increased DDAH1 expression and NO production have been linked to multiple pathological conditions including cancer. However, the prognostic significance of DDAH1 in patients with GC and its function in GC progression remain undefined. In this study, we found that downregulation of DDAH1 was frequently detected in GC tissues and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays confirmed that forced expression of DDAH1 in the GC cells suppressed cell migration and invasion in vitro, as well as metastatic potential in vivo. DDAH1 overexpression inhibited the epithelial–mesenchymal transition process by increasing β‐catenin degradation through the attenuation of Wnt/GSK‐3β signaling. In contrast, knockdown of DDAH1 produced the opposite effect. These findings suggest that DDAH1 functions as a tumor suppressor in GC and may be exploited as a diagnostic and prognostic biomarker for GC.

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“…In addition, de‐regulation of the Wnt pathway has been implicated in the onset and progression of tumorigenesis (Clevers, 2006). A better understanding of the mechanisms underlying Wnt signaling therefore might lay the foundation for novel therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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Wnt/β-Catenin Signaling in Development and Disease

Cited by 5,087 publications

References 115 publications

PAWS 1 controls Wnt signalling through association with casein kinase 1α

PAWS 1 controls Wnt signalling through association with casein kinase 1α

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

ERAD‐dependent control of the Wnt secretory factor Evi

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