Convergence of Wnt, ß-Catenin, and Cadherin Pathways

Nelson, W. James; Nusse, Roel

doi:10.1126/science.1094291

Cited by 2,349 publications

(2,110 citation statements)

References 67 publications

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“…Tumor invasion and EMT are associated with Wnt activation by regulating the b-catenin/E-cadherin complex (Nelson and Nusse, 2004). Moreover, the b-catenin/TCF complex that is induced by the canonical Wnt pathway enhanced the Axin2-dependent pathway and increased stabilization of Snail, a critical regulator of EMT (Yook et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

et al. 2008

Oncogene

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Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3b phosphorylation at Ser9, stabilization and nuclear localization of b-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27 Kip1 phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27 Kip1 phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

et al. 2008

Oncogene

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“…Members of the Wnt family control the proliferation and differentiation of a variety of cell types that can range from progenitor stem cells to mature organ systems [1,2]. More recently, the Wnt family, and in particular Wnt1 signaling, has been closely tied to the control of apoptotic cellular injury.…”

Section: Introductionmentioning

confidence: 99%

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Chong

Maiese

2007

Cellular Signalling

164

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Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during β-amyloid (Aβ 1-42 )exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3β (GSK-3β) and β-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3β and maintains β-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3β, and β-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

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“…Interaction of T-cell factor 7 like 2 (TCF7L2, previously reported as TCF-4) with translocated β-catenin in the nucleus transiently converts TCF7L2 to a transcription factor activator, which induces the expression of target genes, including cyclin D1 and c-myc, in colorectal carcinogenesis [1]. Duval et al (1999;2000) characterized the genomic structure of TCF7L2/TCF-4 in colorectal cancer (CRC) cell lines [2][3].…”

Section: Introductionmentioning

confidence: 99%

Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk

Hazra

Fuchs

Chan

et al. 2008

Cancer Causes Control

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Interaction of TCF7l2 with translocated β-catenin in the nucleus transiently converts TCF7L2 to transcription factor activators, which induce the expression of target genes, including cyclin D1 and c-myc, in colorectal carcinogenesis. We evaluated the association of a polymorphism in TCF7L2 (RS12255372) which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. In the NHS and HPFS control populations, the TCF7L2 T-allele frequency ranged from 28 to 30% and the genotype distribution was in agreement with Hardy-Weinberg equilibrium. Overall, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR=0.63, 95%CI: 0.37-1.08; P for heterogeneity 0.52 for the association in women and men), which was more evident among women (OR=0.39, 95%CI: 0.16 -0.91). The polymorphism was not associated with risk of colorectal adenoma. Furthermore, we observed no evidence of effect modification between the TCF7L2 SNP and covariates such as family history or with genetic variants in the APC Asp1822Val SNP (NHS cancer p-interaction=0.40, NHS adenoma p-interaction 0.10). In summary, the marginal association of TCF7L2 SNP with CRC may be due to chance, but warrants further laboratory and epidemiological investigation.

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Convergence of Wnt, ß-Catenin, and Cadherin Pathways

Cited by 2,349 publications

References 67 publications

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk

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