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

Wu, Changjiang; Xu, Feng; Lu, Michael C.; Morimura, Sohshi; Udey, Mark C.

doi:10.1172/jci88428

Cited by 65 publications

(105 citation statements)

References 46 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hepsin and TMPRSS3 are important for normal hearing1617. Defects in these TTSPs may lead to major diseases such as skin disorders1819, congenital or inflammatory diarrheal diseases202122, iron-deficiency anaemia232425, hypertension26272829, and hearing loss16.…”

mentioning

confidence: 99%

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

Zhang

Yan

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Membrane-bound proteases are essential for epidermal integrity. Human airway trypsin-like protease 4 (HAT-L4) is a type II transmembrane serine protease. Currently, its biochemical property, cellular distribution and physiological function remain unknown. Here we examined HAT-L4 expression and function in vitro and in vivo. In Western analysis, HAT-L4 expressed in transfected CHO cells appeared as a 48-kDa protein. Flow cytometry confirmed HAT-L4 expression on the cell surface with the expected membrane topology. RT-PCR and immunostaining experiments indicated that HAT-L4 was expressed in epithelial cells and exocrine glands in tissues including skin, esophagus, trachea, tongue, eye, bladder, testis and uterus. In the skin, HAT-L4 expression was abundant in keratinocytes and sebaceous glands. We generated HAT-L4 knockout mice by disrupting the Tmprss11f gene encoding HAT-L4. HAT-L4 knockout mice were viable and fertile. No defects were found in HAT-L4 knockout mice in hair growth, wound healing, water repulsion and body temperature regulation. Compared with wild-type controls, HAT-L4-deficient newborn mice had greater body fluid loss and higher mortality in a trans-epidermal body fluid loss test. In metabolic studies, HAT-L4-deficient adult mice drank water more frequently than wild-type controls did. These results indicate that HAT-L4 is important in epidermal barrier function to prevent body fluid loss.

show abstract

mentioning

confidence: 99%

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

Zhang

Yan

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Of note, patients with the syndromic‐form of congenital sodium diarrhea due to SPINT2 mutation show histopathological abnormalities consistent with those of congenital tufting enteropathy that is typically observed in mutation of the EPCAM gene encoding epithelial cell adhesion molecule (EpCAM) . Furthermore, in vitro study has indicated that dysfunction of HAI‐2/SPINT2 results in matriptase‐mediated EpCAM cleavage in Caco‐2 human intestinal epithelial cells . Thus, HAI‐2/SPINT2 may maintain the integrity of intestinal epithelium through regulation of the matriptase activity and EpCAM turnover.…”

Section: Hai‐1/spint1 and Hai‐2/spint2: Emerging Guardians Of Epithelmentioning

confidence: 95%

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

View full text Add to dashboard Cite

The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells.

show abstract

“…31,62 EPCAM is localized at the basolateral membrane of the epithelial cell and plays a role in the regulation of cell adhesion and proliferation via Claudin-7. 101 The syndromic form of CTE is characterized by choanal atresia, rarely intestinal atresia, and chronic diar-rhea. 88 Mutations of the SPINT2 gene that encodes a Kunitztype protease inhibitor have been described in syndromic CTE, as well as in cases of congenital sodium diarrhea, probably representing phenotypic diversity associated with the same mutation.…”

Section: Disorders Of Epithelial Trafficking and Polaritymentioning

confidence: 99%

Advances in Evaluation of Chronic Diarrhea in Infants

et al. 2018

View full text Add to dashboard Cite

Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

show abstract

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

Cited by 65 publications

References 46 publications

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

Advances in Evaluation of Chronic Diarrhea in Infants

Contact Info

Product

Resources

About