ArticlePloS one2014
Functional analysis of a missense mutation in the serine protease inhibitor SPINT2 associated with congenital sodium diarrhea.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- A biochemical difference between HAI-2 variants causing syndromic and non-syndromic Congenital Sodium Diarrhea.PloS one · 2026Article
- Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport.Life science alliance · 2024Article
- Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.The Journal of biological chemistry · 2022Article
- ENaC activation by proteases.Acta physiologica (Oxford, England) · 2022Review
- Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.Journal of Crohn's & colitis · 2021Article
- The Kunitz-type serine protease inhibitor Spint2 is required for cellular cohesion, coordinated cell migration and cell survival during zebrafish hatching gland development.Developmental biology · 2021Article
- TMPRSS13 promotes cell survival, invasion, and resistance to drug-induced apoptosis in colorectal cancer.Scientific reports · 2020Article
- Tufting Enteropathy: A Review of Clinical and Histological Presentation, Etiology, Management, and Outcome.Gastroenterology research and practice · 2020Review
- Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy.Development (Cambridge, England) · 2019Article
- Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine.Communications biology · 2019Article
- Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys).American journal of medical genetics. Part A · 2018Article
- The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells.Scientific reports · 2017Article
- TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections.Biochimie · 2017Review
- Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis.The Journal of clinical investigation · 2017Article
- Selective Inhibition of Prostasin in Human Enterocytes by the Integral Membrane Kunitz-Type Serine Protease Inhibitor HAI-2.PloS one · 2017Article
- The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.Disease models & mechanisms · 2016Review
- N-Glycan Branching Affects the Subcellular Distribution of and Inhibition of Matriptase by HAI-2/Placental Bikunin.PloS one · 2015Article
- The protease inhibitor HAI-2, but not HAI-1, regulates matriptase activation and shedding through prostasin.The Journal of biological chemistry · 2014Article
- Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection.The Journal of biological chemistryReview
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Membrane-bound serine proteases play important roles in different biological processes. Their regulation by endogenous inhibitors is poorly understood. A Y163C mutation in the SPINT2 gene encoding the serine protease inhibitor Hepatocyte Growth Factor Inhibitor HAI-2 is associated with a congenital sodium diarrhea. The functional consequences of this mutation on HAI-2 activity and its physiological targets are unknown. We established a cellular assay in Xenopus laevis oocytes to study functional interactions between HAI-2 and candidate membrane-bound serine proteases expressed in the gastro-intestinal tract. We found that the wild-type form of HAI-2 is a potent inhibitor of nine gastro-intestinal serine proteases. The Y163C mutation in the second Kunitz domain of HAI-2 resulted in a complete loss of inhibitory activity on two intestinal proteases, prostasin and tmprss13. The effect of the mutation of the homologous Y68C in the first Kunitz domain of HAI-2 is consistent with a differential contribution of the two Kunitz domains of HAI-2 in the inhibition of serine proteases. By contrast to the Tyr to Cys, the Tyr to Ser substitution did not change the inhibitory potency of HAI-2, indicating that the thiol-group of the cysteine rather than the Tyr deletion is responsible for the HAI-2 loss of function. Our functional assay allowed us to identify membrane-bound serine proteases as cellular target for inhibition by HAI-2 wild type and mutants, and to better define the role of the Tyr in the second Kunitz domain in the inhibitory activity of HAI-2.
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