Initial activation of EpCAM cleavage viacell-to-cell contact

Denzel, Sabine; Maetzel, Dorothea; Mack, Brigitte; Eggert, Carola; Bärr, Gabriele; Gires, Olivier

doi:10.1186/1471-2407-9-402

Cited by 76 publications

(79 citation statements)

References 37 publications

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“…It has been demonstrated that a proteolytic cleavage of EpCAM by Presenilin 2 releases EpICD, which forms a complex with -catenin and Tcf/Lef leading to an induction of c-Myc and Cyclin A and E expression [371,372].…”

Section: Adherens Complexes In the Context Of -Catenin Signalingmentioning

confidence: 99%

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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Section: Adherens Complexes In the Context Of -Catenin Signalingmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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“…This transcription complex binds the DNA at the lef-1 consensus sites inducing target genes c-myc and cyclin A and E expression [72], and drives cell proliferation. This notion is supported by the EpCAM found in nuclei of colon carcinoma but not of normal tissue [72], and HCT (colon) and MCF-7 (breast) carcinoma cells [65].In addition, analysis for concomitant presence of claudin 7,Co-029,CD44V6 and EpCAM expression in the presence of all four molecules in a complex formation was initially found in colorectal cancer (CRR) and has been shown to facilitate metastasis [108].…”

Section: Epcam Nuclear Signalingmentioning

confidence: 90%

“…EpCAM is a type I transmembrane protein of 314 amino acids (aa)with apparent molecular weight of 40kd [70]. The extracellular domain (EpEX) contain epidermal growth factor-like domain, a thyroglobulin (TY) repeat domain,tansmembrane domain (TM, and a short 26-amino acid intracellular domain (EpICD) (Figure 1) [65,[69][70]. It is encoded by the GA733-2 gene located on the long arm of chromosome 4 [71].…”

Section: Epcam Structurementioning

confidence: 99%

“…EpCAM is an oncogenic receptor [65] that requires regulated intramembrane proteolysis for activation of its signal transduction capacity. EpCAM cleavage is dependent on cell-to-cell contact.…”

Section: Epcam Structurementioning

confidence: 99%

“…EpCAM molecule, a novel oncogenic receptor [65] is shift toward new member family and targeting its antibodies. In this paper, I am delibrating recent advances on EpCAM in this field.…”

Section: Introductionmentioning

confidence: 99%

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EpCAM, a novel oncogenic receptor and its target therapy

Zhu¹,

Yarden²,

Dharmadhikari³

et al. 2018

Trends Cancer Res Chemother

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EpCAM is a cell adhesion molecule. Its structure, its expression and the oncogenic potential, and its signaling network and target therapy were in concise reviewed. EpCAM is expressed in a broad variety of human carcinomas to varying degrees. The identification of EpCAM describing both a protective and a promoting role in carcinogenesis appears to be dependent on the cancer type. In recent advances, in addition to PI3K/akt and Raf/MAPK pathway involving in cell survival, antiapoptosis and proliferation, and malignant initiation and progression three distinct pathway are illustrated: EpCAM/E-cadherin-catenin-actin cytoskeleton,EpCAM/ wint-catenin signaling,and its major EpCAM/nuclear signaling presented by Munz M in 2004. Moreover, more accumulated data are needed in detail mechanism.The data may provide its cancer biology and clinical targeting therapy benefits. Indeed, the use of the EpCAM-specific monoclonal antibody has been successful in increasing disease-free survival in colon and breast cancer patients with minimal residual disease.

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Differential effects of targeting Notch receptors in a mouse model of liver cancer

et al. 2015

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Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question we utilized antibodies to specifically target Notch1, Notch2, Notch3 or Jag1 in a mouse model of primary liver cancer driven by AKT and NRas. We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant hepatocellular carcinoma- and cholangiocarcinoma-like tumors. Inhibition of the Notch ligand Jag 1 had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, as Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples. Conclusions: These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer.

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Initial activation of EpCAM cleavage viacell-to-cell contact

Cited by 76 publications

References 37 publications

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

EpCAM, a novel oncogenic receptor and its target therapy

Differential effects of targeting Notch receptors in a mouse model of liver cancer

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