Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7

Nakatsukasa, Mina; Kawasaki, Satoshi; Yamasaki, Kenta; Fukuoka, Hideki; Matsuda, Akira; Tsujikawa, Motokazu; Tanioka, Hidetoshi; Nagata-Takaoka, Maho; Hamuro, Junji; Kinoshita, Shigeru

doi:10.2353/ajpath.2010.100149

Cited by 77 publications

(87 citation statements)

References 31 publications

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“…The kidney epithelium may thus express an EpCAM-like protein that associates with claudin-7. Tacstd2 is a candidate for such an EpCAM-like molecule, given that it is not only structurally related to EpCAM but it also interacts with claudin-1 and claudin-7 in human tissues and cultured cells and its knockdown reduces the levels of these claudins (Nakatsukasa et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins

Lei¹,

Maeda²,

Tamura³

et al. 2012

Developmental Biology

131

172

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Tight junctions (TJs) connect epithelial cells and form a semipermeable barrier that only allows selective passage of ions and solutes across epithelia. Here we show that mice lacking EpCAM, a putative cell adhesion protein frequently overexpressed in human cancers, manifest intestinal barrier defects and die shortly after birth as a result of intestinal erosion. EpCAM was found to be highly expressed in the developing intestinal epithelium of wild-type mice and to localize to cell-cell junctions including TJs. Claudin-7 colocalized with EpCAM at cell-cell junctions, and the two proteins were found to associate with each other. Claudins 2, 3, 7, and 15 were down-regulated in the intestine of EpCAM mutant mice, with claudin-7 being reduced to undetectable levels. TJs in the mutant intestinal epithelium were morphologically abnormal with the network of TJ strands scattered and dispersed. Finally, the barrier function of the intestinal epithelium was impaired in the mutant animals. These results suggest that EpCAM contributes to formation of intestinal barrier by recruiting claudins to cell-cell junctions.

show abstract

Section: Discussionmentioning

confidence: 99%

EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins

Lei¹,

Maeda²,

Tamura³

et al. 2012

Developmental Biology

131

172

View full text Add to dashboard Cite

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“…Transfection of luciferase reporters into cultured Lrig1 WT and Lrig1-KO mice conjunctival fibroblasts and keratinocytes followed our previous protocol (47). Both fibroblasts and keratinocytes were plated in 24-well culture plates and cultured in DMEM with 10% FBS (fibroblast) or defined KGM (keratinocyte) for 18 to 24 hours before transfection.…”

Section: Methodsmentioning

confidence: 99%

LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis

Nakamura¹,

Hamuro²,

Takaishi³

et al. 2013

J. Clin. Invest.

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Corneal integrity and transparency are indispensable for good vision. Cornea homeostasis is entirely dependent upon corneal stem cells, which are required for complex wound-healing processes that restore corneal integrity following epithelial damage. Here, we found that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is highly expressed in the human holoclone-type corneal epithelial stem cell population and sporadically expressed in the basal cells of ocular-surface epithelium. In murine models, LRIG1 regulated corneal epithelial cell fate during wound repair. Deletion of Lrig1 resulted in impaired stem cell recruitment following injury and promoted a cell-fate switch from transparent epithelium to keratinized skin-like epidermis, which led to corneal blindness. In addition, we determined that LRIG1 is a negative regulator of the STAT3-dependent inflammatory pathway. Inhibition of STAT3 in corneas of Lrig1 -/-mice rescued pathological phenotypes and prevented corneal opacity. Additionally, transgenic mice that expressed a constitutively active form of STAT3 in the corneal epithelium had abnormal features, including corneal plaques and neovascularization similar to that found in Lrig1 -/-mice. Bone marrow chimera experiments indicated that LRIG1 also coordinates the function of bone marrow-derived inflammatory cells. Together, our data indicate that LRIG1 orchestrates corneal-tissue transparency and cell fate during repair, and identify LRIG1 as a key regulator of tissue homeostasis.

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“…For example, in skin matriptase appears to be an upstream activator of prostasin (18), whereas prostasin activates matriptase in the gastrointestinal tract (36). Another possibility is that intestinal epithelium is one of only a few tissues where the EpCAM homolog TROP2 is not coexpressed with EpCAM (40). If EpCAM and TROP2 are functionally redundant, intestinal epithelium would be expected to be particularly vulnerable to loss of EpCAM.…”

Section: Figure 5 Matriptase Cleavage Leads To Dissociation Of Epcammentioning

confidence: 99%

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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Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7

Cited by 77 publications

References 31 publications

EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins

EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins

LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis

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

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