The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin

Friis, Stine; Sales, Katiuchia Uzzun; Schafer, Johanna M.; Vogel, Lotte K.; Kataoka, Hiroaki; Bugge, Thomas H.

doi:10.1074/jbc.m114.574400

Cited by 55 publications

(86 citation statements)

References 54 publications

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“…The cell surface serine protease matriptase is among the enzymes that can be inhibited by HAI-2 indirectly, and possibly directly (15,16). Matriptase is produced as a zymogen, and it becomes fully active only after processing by prostasin, another membrane-associated serine protease, or by matriptase itself (16)(17)(18). Both HAI-2 and the closely related protease inhibitor HAI-1 are regulators of the proteolytic cascade that includes prostasin and matriptase (16,19,20).…”

Section: Introductionmentioning

confidence: 99%

“…SPINT2 encodes a cell membrane-associated Kunitz type 2 serine protease inhibitor, HAI-2, that can regulate the activity of a variety of proteases (15). The cell surface serine protease matriptase is among the enzymes that can be inhibited by HAI-2 indirectly, and possibly directly (15,16). Matriptase is produced as a zymogen, and it becomes fully active only after processing by prostasin, another membrane-associated serine protease, or by matriptase itself (16)(17)(18).…”

Section: Introductionmentioning

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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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: 99%

Section: Introductionmentioning

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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“…Prostasin might be an additional candidate, and evidence indicates that there are mutual and complex interactions between matriptase and prostasin for the activation of their zymogens. 25,49,50 Multiple studies have linked the activation of p38 MAPK to desmosome-associated human skin diseases. For example, pemphigus vulgaris is a skin-blistering disease in humans, and enhanced phosphorylation of p38 MAPK is observed in pemphigus vulgaris skin.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Kawaguchi

Kanemaru

Sawaguchi

et al. 2015

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membraneassociated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI-1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1edeficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2edependent p38 mitogen-activated protein kinase signaling. Human skin protects the body from both water loss and mechanical damage. This barrier function is primarily accomplished by the epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes. 1 To achieve the barrier functions, keratinocytes form dynamic and strong cell-cell junctions in which desmosomes and the network of keratin intermediate filaments (KIFs) are essential to maintain junctional integrity. 2 KIFs are anchored to the cytoplasm and interact with desmosomal cell-cell contacts at the plasma membrane. These are important for mechanical stability of cell-cell contacts between keratinocytes. 3 Disturbance of the integrity of the KIF network leads to skin-blistering diseases, such as epidermolysis bullosa simplex. 4 Although it is not known how KIF disassembly is regulated, recent studies suggested that p38 mitogen-activated protein kinase (MAPK) signaling is involved in these processes. 4e6 The p38 is a member of the MAPK family. It is present in epithelial cells, responds rapidly to various types of stresses,

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“…It potently inhibits many serine proteases with subnanomolar affinities (66) and is believed to be a physiological inhibitor of hepatocyte growth factor (HGF) activator (67) as well as hepsin (68) and matriptase (69,70), two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-hepatocyte growth factor/scatter factor (pro-HGF/SF) into the two-chain active signaling heterodimer. Additionally, HAI2 is a physiological inhibitor of prostasin, a glycosylphosphatidylinositol-anchored protease involved in regulation of matriptase activation and shedding (71,72). HAI2-KD1, shown here to be a good substrate for mesotrypsin, has been found to be the domain responsible for inhibition of HGF activator (67).…”

Section: Discussionmentioning

confidence: 99%

Sequence and Conformational Specificity in Substrate Recognition

Pendlebury

Wang

Henin

et al. 2014

Journal of Biological Chemistry

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Background: Mesotrypsin targets protease inhibitors as substrates; substrate recognition depends on sequence and conformational motifs. Results: Mesotrypsin cleaves three human Kunitz domains as specific substrates, but other similarly shaped substrates are cleaved less efficiently. Conclusion: Substrate conformation aids recognition by mesotrypsin but is not sufficient for efficient cleavage. Significance: Mesotrypsin cleavage of human Kunitz domains may contribute to cancer progression.

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The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin

Cited by 55 publications

References 54 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

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Sequence and Conformational Specificity in Substrate Recognition

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