Essential Role of Endocytosis of the Type II Transmembrane Serine Protease TMPRSS6 in Regulating Its Functionality

SummaryMatriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-related protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. Here we have investigated cyclic microproteins of the squash Momordica cochinchinensis trypsin-inhibitor family (generated by total chemical synthesis) and found MCoTI-II to be a high-affinity (Ki 9 nM) and highly selective (> 1,000-fold) inhibitor of matriptase. MCoTI-II efficiently inhibited the proteolytic activation of pro-hepatocyte growth factor (HGF) by matriptase but not by hepsin, in both purified and cell-based systems, and inhibited HGF-dependent cell scattering. MCoTI-II also selectively inhibited the invasion of matriptase-expressing prostate cancer cells. Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptase-dependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance.

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Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Molecular and Cellular Biology ◽

10.1128/mcb.26.3.965-975.2006 ◽

2006 ◽

Vol 26 (3) ◽

pp. 965-975 ◽

Cited By ~ 105

Author(s):

Tom S. Kim ◽

Cynthia Heinlein ◽

Robert C. Hackman ◽

Peter S. Nelson

Keyword(s):

Serine Protease ◽

Serine Proteases ◽

Biological Activities ◽

Type Ii ◽

Phenotypic Analysis ◽

Normal Prostate ◽

Prostate Hyperplasia ◽

Transmembrane Serine Protease

ABSTRACT Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2 −/− mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 −/− mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 −/− mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 −/− mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

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The Type II Transmembrane Serine Protease, Matriptase-2: Possible Links to Cancer?

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520611009010064 ◽

2010 ◽

Vol 10 (1) ◽

pp. 64-69 ◽

Cited By ~ 13

Author(s):

Andrew Sanders ◽

Siobhan Webb ◽

Christian Parr ◽

Malcolm Mason ◽

Wen Jiang

Keyword(s):

Serine Protease ◽

Type Ii ◽

Transmembrane Serine Protease

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TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections

Biological Chemistry ◽

10.1515/hsz-2012-0155 ◽

2012 ◽

Vol 393 (9) ◽

pp. 907-914 ◽

Cited By ~ 17

Author(s):

Anke Ohler ◽

Christoph Becker-Pauly

Keyword(s):

Serine Protease ◽

Serine Proteases ◽

Viral Infections ◽

Proteolytic Enzymes ◽

Metastatic Potential ◽

Influenza Viruses ◽

Type Ii ◽

Serine Protease Family ◽

Transmembrane Serine Protease ◽

Almost All

Abstract Proteolytic enzymes are involved in almost all biological processes reflecting their importance in health and disease. The human genome contains nearly 600 protease-encoding genes forming more than 2% of the total human proteome. The serine proteases, with about 180 members, built the oldest and second largest family of human proteases. Ten years ago, a novel serine protease family named the type II transmembrane family (TTSP) was identified. This minireview summarizes the up-to-date knowledge about the still growing TTSPs, particularly focusing on the pathophysiological functions of the family member type II transmembrane serine protease (TMPRSS) 4. Recent studies provided important data on TMPRSS4 activity associated with the spreading of influenza viruses, mediated by the cleavage of hemagglutinin. Progression and metastatic potential of several cancers is concordant with an increased expression of TMPRSS4, though being a possible diagnostic marker. However, to benefit from TMPRSS4 as a therapeutic target, more data concerning its physiological relevance are needed, as done by a specific morpholino knockdown in zebrafish embryos.

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Interaction of Protein C Inhibitor with the Type II Transmembrane Serine Protease Enteropeptidase

PLoS ONE ◽

10.1371/journal.pone.0039262 ◽

2012 ◽

Vol 7 (6) ◽

pp. e39262 ◽

Cited By ~ 8

Author(s):

Thomas A. Prohaska ◽

Felix C. Wahlmüller ◽

Margareta Furtmüller ◽

Margarethe Geiger

Keyword(s):

Serine Protease ◽

Protein C ◽

Type Ii ◽

Protein C Inhibitor ◽

Transmembrane Serine Protease

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Autosomal Recessive Ichthyosis with Hypotrichosis Caused by a Mutation in ST14, Encoding Type II Transmembrane Serine Protease Matriptase

The American Journal of Human Genetics ◽

10.1086/512487 ◽

2007 ◽

Vol 80 (3) ◽

pp. 467-477 ◽

Cited By ~ 130

Author(s):

Lina Basel-Vanagaite ◽

Revital Attia ◽

Akemi Ishida-Yamamoto ◽

Limor Rainshtein ◽

Dan Ben Amitai ◽

...

Keyword(s):

Serine Protease ◽

Autosomal Recessive ◽

Type Ii ◽

Transmembrane Serine Protease ◽

Recessive Ichthyosis

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Gene of the month: TMPRSS2 (transmembrane serine protease 2)

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206987 ◽

2020 ◽

Vol 73 (12) ◽

pp. 773-776 ◽

Cited By ~ 4

Author(s):

Michelle Thunders ◽

Brett Delahunt

Keyword(s):

Serine Protease ◽

Viral Entry ◽

Fusion Gene ◽

Related Gene ◽

Diverse Range ◽

Angiotensin Converting Enzyme 2 ◽

Viral Spread ◽

Transmembrane Serine Protease ◽

Oncogenic Transcription Factor

Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

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