A p120-catenin–CK1ε complex regulates Wnt signaling

Casagolda, David; Valle-Pérez, Beatriz Del; Valls, Gabriela; Lugilde, Ero; Vinyoles, Meritxell; Casado‐Vela, Juan; Solanas, Guiomar; Batlle, Eduard; Reynolds, Albert B.; Casal, J. Ignacio; Herreros, Antonio Garcı́a de; Duñach, Mireia

doi:10.1242/jcs.067512

Cited by 66 publications

(115 citation statements)

References 40 publications

(43 reference statements)

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“…4). CTNND1 is membrane-bound and plays a role in adherens junctions by regulating E-cadherin (41); it has also been shown to regulate WNT signaling (42). GNAQ is a cytoplasmic guaninine-nucleotide binding protein that signals to RhoA and is implicated in cell proliferation and migration (43).…”

Section: Ccgs In Sb-driven Pancreatic Cancer Predict Human Pancreaticmentioning

confidence: 99%

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann

Ward

Yew

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

205

219

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Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma. P ancreatic ductal adenocarcinoma is one of the most deadly forms of cancer. In the United States, the rate of mortality is nearly equal to the rate of new diagnoses (1). Early disease detection is rare, and of those patients diagnosed with early-stage disease, only 20% are candidates for surgical resection. Approximately 50% of patients develop highly metastatic disease, for which current treatment regimens provide little increase in longevity (2). Clearly, there is a need for better biomarkers of disease and the identification of new therapeutic targets, particularly for metastatic disease.Human pancreatic cancer develops from preinvasive neoplasias, typically intraepithelial neoplasias (PanINs), although intraductal papillary mucinous neoplasia and mucinous cystic neoplasia can also give rise to adenocarcinoma (3). The majority of pancreatic adenocarcinoma is of ductal origin and contains a large desmoplastic component thought to promote tumorigenesis by modulating the tumor microenvironment. Oncogenic KRAS mutations are found in 90% of human tumors, and they appear in early PanIN (4). The accumulation of additional inactivating driver mutations in P16/CDKN2A, TP53, and SMAD4 occurs with high frequency in later-stage PanIN, and these mutations are likely required for tumor progression to invasive adenocarcinoma.Recent high-throughput sequencing efforts have shown that the majority of somatic point mutations in primary pancreatic adenocarcinoma are missense mutations and that most occur at low frequency (5). Pancreatic cancers exhibit a very unstable genome, and through whole-genome...

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Section: Ccgs In Sb-driven Pancreatic Cancer Predict Human Pancreaticmentioning

confidence: 99%

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann

Ward

Yew

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

205

219

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“…Ncadherin [304] and E-cadherin [305] were shown to be able to directly associate with Lrp5/6. Binding of Wnt morphogens to the Frizzled-LRP5/6 induces a CK1 -dependent phosphorylation of both LRP5/6 and E-cadherin [306] inducing a dissociation of LRP5/6 from E-cadherin [230].…”

Section: Connections Between the Wnt-frizzled-lrp5/6 Signalosome Andmentioning

confidence: 99%

“…IC261 was shown to bind tubulin and act as an inhibitor of microtubules polymerization [308]. Intriguingly, p120 that has a major cytoplasmic function at the cytoplasmic end of Ecadherin, also interacts with the Wnt signalosome making it an important linker protein [305]. A depletion of p120 prevents interactions between CK1 and LRP5/6, disrupting LRP5/6 phosphorylation and AXIN recruitment to the LRP5/6 signalosome, leading ultimately to increased -catenin degradation [305].…”

Section: Connections Between the Wnt-frizzled-lrp5/6 Signalosome Andmentioning

confidence: 99%

“…Intriguingly, p120 that has a major cytoplasmic function at the cytoplasmic end of Ecadherin, also interacts with the Wnt signalosome making it an important linker protein [305]. A depletion of p120 prevents interactions between CK1 and LRP5/6, disrupting LRP5/6 phosphorylation and AXIN recruitment to the LRP5/6 signalosome, leading ultimately to increased -catenin degradation [305]. An absence of p120 also has been reported to disrupt CK1 -mediated phosphorylation of Dvl2 [305].…”

Section: Connections Between the Wnt-frizzled-lrp5/6 Signalosome Andmentioning

confidence: 99%

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Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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“…Phosphorylation on S268 and S269 destabilizes p120catenin -cadherin interactions and leads to p120catenin accumulation in the nucleus. Consequently, it represses Kaiso activity to activate the pro-tumourigenic and pro-invasive Wnt signalling pathway [146,147].…”

Section: (B) P120catenin Interacts With Kaiso To Control Gene Transcrmentioning

confidence: 99%

p120catenin alteration in cancer and its role in tumour invasion

Péglion

Etienne-Manneville

2013

Phil. Trans. R. Soc. B

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Since its discovery in 1989 as a substrate of the Src oncogene, p120catenin has been revealed as an important player in cancer initiation and tumour dissemination. p120catenin regulates a wide range of cellular processes such as cell–cell adhesion, cell polarity and cell proliferation and plays a pivotal role in morphogenesis, inflammation and innate immunity. The pleiotropic effects of p120catenin rely on its interactions with numerous partners such as classical cadherins at the plasma membrane, Rho-GTPases and microtubules in the cytosol and transcriptional modulators in the nucleus. Alterations of p120catenin in cancer not only concern its expression level but also its intracellular localization and can lead to both pro-invasive and anti-invasive effects. This review focuses on the p120catenin-mediated pathways involved in cell migration and invasion and discusses the potential consequences of major cancer-related p120catenin alterations with respect to tumour spread.

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A p120-catenin–CK1ε complex regulates Wnt signaling

Cited by 66 publications

References 40 publications

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

p120catenin alteration in cancer and its role in tumour invasion

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