Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

Buzza, Marguerite S.; Netzel‐Arnett, Sarah; Shea‐Donohue, Terez; Zhao, Aiping; Lin, Chen Yong; List, Karin; Szabo, Roman; Fasano, Alessio; Bugge, Thomas H.; Antalis, Toni M.

doi:10.1073/pnas.0903923107

Cited by 154 publications

(213 citation statements)

References 28 publications

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“…E-cadherin was stained and visualized in the Cy3 channel to delineate the epithelium. The matriptase/ST14 antibody did not show any reactivity with stromal components, reaffirming data documenting that matriptase is an epithelium specific marker (12). The active-site specific A11-AF488 did not detect active matriptase in the healthy colon tissue (Fig.…”

Section: Resultssupporting

confidence: 79%

“…Matriptase is expressed in a range of normal human tissue types with high transcript levels found in the colon, rectum, and pancreas (11). In healthy tissue, matriptase is responsible for regulating barrier formation in the skin, intestines, and during embryonic development (10,12,13). The proteolytic activity of matriptase is closely regulated by its cognate macromolecular inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1) (8).…”

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confidence: 99%

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Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

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

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Proteases responsible for the increased peritumoral proteolysis associated with cancer represent functional biomarkers for monitoring tumorigenesis. One attractive extracellular biomarker is the transmembrane serine protease matriptase. Found on the surface of epithelial cells, the activity of matriptase is regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). Quantitative mass spectrometry allowed us to show that, in selected cancers, HAI-1 expression decreases, leading to active matriptase. A preclinical probe specific for the measurement of emergent active matriptase was developed. Using an active-site-specific, recombinant human antibody for matriptase, we found that the selective targeting of active matriptase can be used to visualize the tumorigenic epithelium. Live-cell fluorescence imaging validated the selectivity of the antibody in vitro by showing that the probe localized only to cancer cell lines with active matriptase on the surface. Immunofluorescence with the antibody documented significant levels of active matriptase in 68% of primary and metastatic colon cancer sections from tissue microarrays. Labeling of the active form of matriptase in vivo was measured in human colon cancer xenografts and in a patient-derived xenograft model using near-infrared and single-photon emission computed tomography imaging. Tumor uptake of the radiolabeled antibody, 111 In-A11, by active matriptase was high in xenografts (28% injected dose per gram) and was blocked in vivo by the addition of a matriptase-specific variant of ecotin. These findings suggest, through a HAI-1-dependent mechanism, that emergent active matriptase is a functional biomarker of the transformed epithelium and that its proteolytic activity can be exploited to noninvasively evaluate tumorigenesis in vivo.cancer biomarker | molecular imaging

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Section: Resultssupporting

confidence: 79%

mentioning

confidence: 99%

Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

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

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“…16 Recently, a trypsin-like transmembrane serine protease, matriptase, has emerged as an important molecule that is required for the homeostasis of multiple simple and stratified epithelia, including intestinal epithelium. 17,21 This study provides evidence that the membrane-bound serine protease inhibitor HAI-1/SPINT1 is also required to maintain epithelial integrity in intestinal tissue. Indeed, matriptase is a well-known cognate protease of HAI-1/SPINT1, and the activity of matriptase is tightly regulated by this membrane-bound inhibitor.…”

Section: Discussionmentioning

confidence: 84%

“…33 Regarding the mechanism underlying these observations, matriptase hypomorphic mice are also susceptible to DSS colitis, again suggesting important roles for optimal matriptase activity in intestinal epithelial homeostasis and integrity. 21 However, expression of claudin-2, a leaky claudin that was up-regulated in the intestine of matriptase hypomorhic mice, 21 was not apparently enhanced in Hai-1/Spint1-deficient intestine (data not shown). Altered pericellular activation of HGF, which can be activated by matriptase or HGFAC, 10,34 may be involved in these phenotypes, which should be tested in a future study.…”

Section: Discussionmentioning

confidence: 87%

Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

Kawaguchi

Takeda

Hoshiko

et al. 2011

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1 LoxP homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter. Although the resulting mice had normal development and appearance, crypts in the proximal aspect of the colon, including the cecum, exhibited histologic abnormalities and increased apoptosis and epithelial cell turnover accompanied by increased intestinal permeability. Distended endoplasmic reticula were observed ultrastructurally in some crypt epithelial cells, indicative of endoplasmic reticular stress. To study the role of HAI-1/SPINT1 in mucosal injury, we induced colitis by adding dextran sodium sulfate to the drinking water. After dextran sodium sulfate treatment, intestine-specific HAI-1/SPINT1-deficient mice had more severe symptoms and a significantly lower survival rate relative to control mice. These results suggest that HAI-1/SPINT1 plays an important role in maintaining colonic epithelium integrity.

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“…In general, low levels of trypsin and trypsin-like proteases such as cap1 and matriptase (cap3) are potent inducers of TJ formation in a variety of epithelia (25,(46)(47)(48). The constitutive cap1 KO mice died within 60 d after birth due to impaired skin barrier function and fatal dehydration (49).…”

Section: Discussionmentioning

confidence: 99%

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Gong

Yang³

et al. 2014

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

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The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a proteasechannel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.chloride channel | epithelium | hypertension C hloride is the most abundant extracellular anion and thereby determines extracellular fluid volume (ECFV) and blood pressure (BP) (1, 2). The kidney plays a vital role in ECFV and BP control through complex regulatory mechanisms acting upon ion channels and transporters located in the aldosterone-sensitive distal nephron (ASDN) (3, 4). The ASDN comprises the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD). The primary chloride transport mechanism in the DCT is through the thiazide-sensitive Na + /Cl − cotransporter (NCC) to reabsorb Cl − coupled with equal moles of Na + (5). The chloride transport mechanism in the CNT and CD, on the other hand, has been under debate for many years. Recent advances have identified an electroneutral transport pathway for chloride using the Cl − /bicarbonate exchanger (Slc26a4; pendrin) (6) and the Na + -driven Cl − /bicarbonate exchanger (Slc4a8; NDCBE) (7) in the β-intercalated cells (ICs) of CNT and CD. However, such an electroneutral pathway is not able to couple Cl − reabsorption with epithelial sodium channel (ENaC)-based Na + reabsorption that takes place in the principal cells (PCs) of CNT and CD (8), despite many efforts to connect ENaC and pendrin gene expression through endocrine or paracrine mechanisms (9, 10). We and others have previously demonstrated the presence of a paracellular Cl − pathway or "chloride shunt" in vitro in the CNT and CD cells (11,12). The paracellular Cl − channel is made of a key claud...

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Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

Cited by 154 publications

References 28 publications

Imaging a functional tumorigenic biomarker in the transformed epithelium

Imaging a functional tumorigenic biomarker in the transformed epithelium

Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

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