Epithelial Cell Adhesion Molecule (EpCAM) Regulates Claudin Dynamics and Tight Junctions

Wu, Changjiang; Mannan, Poonam; Lu, Michael C.; Udey, Mark C.

doi:10.1074/jbc.m113.457499

Cited by 112 publications

(145 citation statements)

References 50 publications

(54 reference statements)

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“…Mice with germline null mutations in Epcam develop the murine equivalent of CTE and die within 2 weeks after birth (10,11). Consistent with EpCAM's claudin-stabilizing effects (12), intestinal expression of selected claudins, including claudin-7, is markedly decreased in mice and humans with EPCAM mutations (3,10). The strong similarities between the phenotypes of Epcam and Cldn7 knockout mice suggest that EpCAM-claudin interactions are extremely important in the intestine (8,13,14).…”

Section: Introductionmentioning

confidence: 60%

“…Previous studies have identified the cell surface protease matriptase as an important regulator of tight junction composition and function, but detailed molecular mechanisms that link matriptase and tight junctions have not been delineated (21,22). EpCAM also modulates tight junctions, albeit in a reciprocal fashion (10,12). Whereas inhibition of expression of matriptase in Caco-2 cell monolayers increased permeability and decreased transepithelial electrical resistance (TEER) (21), inhibition of EpCAM expression by Caco-2 cells enhanced TEER in conjunction with decreased claudin-7 expression (12).…”

Section: Discussionmentioning

confidence: 99%

“…Caco-2 cells, T84 cells, and Caco-2 cells that are stable expressers of EpCAM shRNA have been described previously (12). Caco-2 cells were grown in DMEM containing 10% FBS, 15 mM HEPES, and nonessential amino acids (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

Wu¹,

Xu²,

Lu³

et al. 2017

Journal of Clinical Investigation

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Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction-associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated.

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Section: Introductionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

Wu¹,

Xu²,

Lu³

et al. 2017

Journal of Clinical Investigation

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“…Others, epithelial-specific Ets-1 and Sp1 play an active role in EpCAM promoter regulation 37 , while transcription factor nuclear factor-kappa B（NF-KB）and p53 have been described as transcriptional repressor of EpCAM 47 . TACE-dependent EGFR axis 57 , Claudin-7 and claudin-1 trafficked into lysosomes 58 and presenillins mediate PI3K/akt and ERK activation via select signaling receptors 59 ,which present a highlight mechanism in cancer. The emerging function of EpCAM in cell proliferation, migration and possibly cancer initiation broadens the interest to use EpCAM as an immune target, antibodybased clinical trials and in 2009, the European Medicines Agency approved the use of tri functional bi specific antibody Catumaxomab, which binds to EpCAM oncogenic receptor and enhances the immunological response against EpCAM-positive cells in malignant ascites 43 .…”

Section: Signal Transduction By Epcam Oncogenic Receptor and Its Targmentioning

confidence: 99%

EpCAM- AN OLD CANCER ANTIGEN, TURNED ONCOGENIC RECEPTOR AND ITS TAGETING IMMUNOTHERAPY

Zhu

2018

UJPR

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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. In recent advances,in addition to PI3K/akt and Raf/MAPK pathway involving in cell survival,anti-apoptosis and proliferation,and malignant initiation and progression(see figure by Zhu,1986-91), 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.

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“…TACE-dependent EGFR axis [109,110], Claudin-7 and claudin-1 trafficked into lysosomes [111] and presenillins mediate PI3K/akt and ERK activation via select signaling receptors [112], which present a highlight mechanism in cancer.…”

Section: Epcam Nuclear Signalingmentioning

confidence: 99%

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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Epithelial Cell Adhesion Molecule (EpCAM) Regulates Claudin Dynamics and Tight Junctions

Cited by 112 publications

References 50 publications

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

EpCAM- AN OLD CANCER ANTIGEN, TURNED ONCOGENIC RECEPTOR AND ITS TAGETING IMMUNOTHERAPY

EpCAM, a novel oncogenic receptor and its target therapy

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