Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Szabo, Roman; Molinolo, Alfredo A.; List, Karin; Bugge, Thomas H.

doi:10.1038/sj.onc.1209966

Cited by 129 publications

(152 citation statements)

References 26 publications

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“…Our results are consistent with findings in other transmembrane serine proteases. Oberst et al (23) have shown that an N-glycosylation site in the protease domain is critical for the activation of matriptase, a type II transmembrane serine protease essential for the development of multiple epithelial tissues (37)(38)(39). Similarly, Zheng et al (24,25) have shown that N-glycans in the enteropeptidase protease domain are important for the apical targeting of this digestive enzyme.…”

Section: Discussionmentioning

confidence: 99%

Role of Glycosylation in Corin Zymogen Activation

Liao

Wang

Chen

et al. 2007

Journal of Biological Chemistry

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The cardiac serine protease corin is the pro-atrial natriuretic peptide convertase. Corin is made as a zymogen, which is activated by proteolytic cleavage. Previous studies showed that recombinant human corin expressed in HEK 293 cells was biologically active, but activated corin fragments were not detectable, making it difficult to study corin activation. In this study, we showed that recombinant rat corin was activated in HEK 293 cells, murine HL-1 cardiomyocytes, and rat neonatal cardiomyocytes. In these cells, activated corin represented a small fraction of the total corin molecules. The activation of recombinant rat corin was inhibited by small molecule trypsin inhibitors but not inhibitors for matrix metalloproteinases or cysteine proteases, suggesting that a trypsin-like protease activated corin in these cells. Glycosidase digestion showed that rat and human corin proteins contained substantial N-glycans but little O-glycans. Treatment of HEK 293 cells expressing rat corin with tunicamycin prevented corin activation and inhibited its pro-atrial natriuretic peptide processing activity. Similar effects of tunicamycin on endogenous corin activity were found in HL-1 cells. Mutations altering the two N-glycosylation sites in the protease domain of rat corin prevented its activation in HEK 293 and HL-1 cells. Our results indicate that N-linked oligosaccharides play an important role in corin activation.

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Section: Discussionmentioning

confidence: 99%

Role of Glycosylation in Corin Zymogen Activation

Liao

Wang

Chen

et al. 2007

Journal of Biological Chemistry

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“…Background buffer subtraction and conversion of the data to absolute scale by use of water as a primary standard was performed using the SUPERSAXS program package. 3 The instrumental sample-to-detector distance was set to 640 cm, giving a q range of 0.01-0.345 Å Ϫ1 , where q is the length of the scattering vector, defined as q ϭ 4sin()/, where is the x-ray wavelength at 1.54 Å and 2 is the scattering angle between the incident and scattered beam. The final intensity is I(q), in units of cm Ϫ1 .…”

Section: Saxs Data Collection and Analysismentioning

confidence: 99%

“…The deletion of the 60-loop (chymotrypsin template numbering) was accomplished by substitution of DDRGFR (Asp 660 -Arg 665 ) with GG using site-directed mutagenesis. To introduce the StrepII tag in the C terminus of the matriptase catalytic domain, the StrepII tag (SAWSHPQFEK) was fused to the C terminus with an additional (GS) 3 linker.…”

Section: Recombinant Protein Productionmentioning

confidence: 99%

“…HAI-1 was initially identified as an inhibitor co-purifying with hepatocyte growth factor activator (HGFA) (8) and was later purified from human milk in complex with the type II transmembrane serine protease matriptase (9). The physiological importance of the HAI-1-matriptase relationship was cemented in genetic mouse studies, where simultaneous ablation of matriptase rescues the placental defect caused by a lack of HAI-1 (3). It has also been proposed that HAI-1 inhibits the glycophosphatidylinositol membrane-anchored serine protease prostasin (10).…”

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confidence: 99%

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Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1

Hong

Meulemeester

Jacobi

et al. 2016

Journal of Biological Chemistry

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Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knockout mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain).

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“…In fact, mice lacking HAI-1/SPINT1 have completely impaired placental labyrinth layer development, and the concomitant deletion of the matriptase/St14 gene rescues this phenotype. 6,7 In mouse skin, HAI-1/SPINT1 interacts with matriptase to play a central role in regulated keratinization of the epidermis. 8,9 The participation of HAI-1/SPINT1 in the maintenance of epidermal integrity in zebrafish was also demonstrated.…”

mentioning

confidence: 99%

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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Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Cited by 129 publications

References 26 publications

Role of Glycosylation in Corin Zymogen Activation

Role of Glycosylation in Corin Zymogen Activation

Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1

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

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