Affinage

TMPRSS2

Transmembrane protease serine 2 · UniProt O15393

Length
492 aa
Mass
53.9 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMPRSS2 is a type II transmembrane serine protease, expressed under androgen receptor control predominantly in prostate and lung epithelia, that functions at the cell surface to proteolytically activate viral glycoproteins and endogenous substrates. Its serine protease domain cleaves the spike proteins of SARS-CoV-2, SARS-CoV, influenza hemagglutinin, and HCV entry factors, enabling plasma-membrane-route viral fusion; TMPRSS2 knockout in mice strongly reduces SARS-CoV-2 replication in the respiratory tract, and small-molecule inhibitors (camostat, nafamostat, N-0385) block this entry pathway (PMID:32142651, PMID:36243815, PMID:35344983). Beyond its catalytic role, TMPRSS2 serves as a proteinaceous entry receptor for HCoV-HKU1, binding the viral RBD through its catalytic groove even when proteolytically inactive, with structural rearrangements upon zymogen activation dramatically increasing binding affinity (PMID:37879362, PMID:38964326). In prostate cancer, recurrent chromosomal rearrangements fuse the androgen-responsive TMPRSS2 promoter to ETS family oncogenes (most commonly ERG), driving androgen-dependent ERG overexpression that recruits BAF chromatin-remodeling complexes genome-wide and promotes invasion through the plasminogen activation pathway (PMID:16254181, PMID:30078722, PMID:18283340).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing TMPRSS2 as a novel transmembrane serine protease with androgen-regulated expression in prostate epithelium defined the gene's identity, domain architecture, and hormonal control before any functional role was known.

    Evidence cDNA microarray of androgen-treated prostate cancer cells, Northern blot, in situ hybridization

    PMID:10485450

    Open questions at the time
    • No endogenous substrate identified
    • Catalytic activity not directly demonstrated
    • Expression in non-prostate tissues not systematically surveyed
  2. 2005 High

    Discovery that recurrent TMPRSS2-ETS gene fusions place oncogenic ETS transcription factors under androgen-responsive TMPRSS2 promoter control established a new paradigm for epithelial cancer-associated gene fusions and explained the frequent ETS overexpression in prostate cancer.

    Evidence Outlier expression bioinformatics, RT-PCR, FISH on prostate cancer tissues

    PMID:16254181

    Open questions at the time
    • Mechanism by which fusion drives transformation not yet defined
    • Frequency across ethnic groups unknown
    • Cooperating oncogenic events not identified
  3. 2008 High

    Demonstrating that the TMPRSS2-ERG fusion product drives prostate epithelial cell invasion through the plasminogen activation pathway resolved how ETS overexpression contributes to prostate cancer aggressiveness.

    Evidence Transgenic mouse model, ERG knockdown in VCaP cells, invasion assays, transcriptional profiling

    PMID:18283340

    Open questions at the time
    • Whether ERG suffices for full transformation or requires cooperating events
    • Direct ERG transcriptional targets mediating invasion incompletely mapped
  4. 2010 Medium

    Showing that androgen treatment can induce TMPRSS2-ERG chromosomal fusions in non-malignant prostate cells addressed whether the fusion is an initiating event or consequence of malignancy, establishing that androgen-driven spatial proximity of the TMPRSS2 and ERG loci enables rearrangement prior to transformation.

    Evidence RT-PCR for fusion transcripts after androgen treatment, FISH for gene proximity

    PMID:20947519

    Open questions at the time
    • Frequency of de novo fusion induction in normal cells very low
    • DNA repair defect requirement not tested
    • Not independently replicated
  5. 2013 High

    Identification of the upstream androgen-responsive enhancer with ARE and GATA2 sites, plus a functional SNP (rs8134378) modulating AR binding, provided the cis-regulatory architecture explaining how androgens control TMPRSS2 transcription and how genetic variation affects expression levels.

    Evidence BAC reporters, DNase I footprinting, ARE mutagenesis, AR binding assays, SNP functional analysis

    PMID:24109594

    Open questions at the time
    • Contribution of additional distal enhancers not fully mapped
    • Tissue-specific enhancer usage (prostate vs. lung) not compared
  6. 2015 High

    Demonstrating that TMPRSS2 proteolytic activity at the cell surface activates HCV infection and cleaves influenza HA established TMPRSS2 as a broadly relevant host protease for respiratory and hepatotropic viruses beyond coronaviruses.

    Evidence Stable wild-type vs. catalytic mutant expression, HCV infection assays, HA cleavage assays, pseudovirus entry with cathepsin inhibition

    PMID:25203900 PMID:26379044

    Open questions at the time
    • In vivo relevance for HCV not demonstrated
    • Full range of viral substrates not surveyed
  7. 2017 High

    Showing that clinical HCoV-OC43 and HCoV-HKU1 isolates preferentially use TMPRSS2 rather than cathepsins for spike priming established that the TMPRSS2-dependent plasma membrane entry route is the physiologically dominant pathway for human coronaviruses in airway epithelia.

    Evidence Infection assays with clinical vs. culture-adapted strains, pharmacological pathway dissection, air-liquid interface cultures

    PMID:29217279

    Open questions at the time
    • Genetic knockout confirmation not performed
    • Whether other TTSPs can compensate not tested
  8. 2017 High

    Identification of FOXO1 as a direct binding partner and functional inhibitor of ERG activity, with in vivo validation that Foxo1 loss cooperates with ERG to drive prostate neoplasia, revealed a tumor-suppressive checkpoint on TMPRSS2-ERG oncogenic signaling.

    Evidence Co-IP, reporter assays, siRNA knockdown, invasion assays, genetically engineered mouse model

    PMID:28986382

    Open questions at the time
    • How FOXO1-ERG interaction is regulated by upstream signals incompletely defined
    • Relevance in human prostate cancer progression not directly tested
  9. 2018 High

    Demonstrating that the TMPRSS2-ERG fusion protein directly recruits BAF (SWI/SNF) chromatin-remodeling complexes to ETS motifs genome-wide resolved the chromatin-level mechanism by which ERG overexpression reprograms the prostate cancer epigenome.

    Evidence Reciprocal Co-IP, ChIP-seq, prostate organoid model with BAF perturbation

    PMID:30078722

    Open questions at the time
    • Which BAF subunit directly contacts ERG not identified
    • Whether BAF retargeting is reversible upon ERG depletion not shown
  10. 2020 High

    The landmark demonstration that SARS-CoV-2 requires TMPRSS2 for spike priming and cell entry—blockable by camostat—established TMPRSS2 as a therapeutic target for COVID-19 and explained the virus's tropism for TMPRSS2-expressing airway cells.

    Evidence Pseudovirus and authentic virus infection, TMPRSS2-expressing vs. non-expressing cells, camostat inhibition

    PMID:32142651

    Open questions at the time
    • In vivo efficacy of camostat not yet demonstrated in this study
    • Relative contribution vs. cathepsin pathway in different tissues unknown
  11. 2021 High

    Identification of endogenous inhibitors alpha-1 antitrypsin and HAI-2 as direct TMPRSS2-binding inhibitors that suppress both viral entry and cancer cell invasion, respectively, revealed physiological regulatory mechanisms controlling TMPRSS2 proteolytic activity in airway and prostate contexts.

    Evidence Co-IP/MS for HAI-2, bronchoalveolar lavage screen for α1AT, enzyme activity assays, pseudovirus/authentic virus infection, xenograft models

    PMID:32778768 PMID:33741941

    Open questions at the time
    • Whether α1AT deficiency predisposes to severe COVID-19 not causally demonstrated
    • Stoichiometry of HAI-2–TMPRSS2 complex not determined
  12. 2021 High

    Showing that EZH2 methylates the TMPRSS2-ERG fusion product at K362, enhancing ERG DNA binding and transcriptional activity downstream of PTEN loss/AKT signaling, integrated the TMPRSS2-ERG axis with PI3K and Polycomb pathways in prostate cancer progression.

    Evidence In vitro methylation assays, K362 mutagenesis, ChIP-seq, Co-IP, genetically engineered mouse model

    PMID:34230470

    Open questions at the time
    • Whether K362 methylation is targetable therapeutically not tested
    • Dynamics of methylation during disease progression unknown
  13. 2022 High

    The crystal structure of TMPRSS2 with nafamostat revealed the substrate-binding pocket architecture and enabled structure-guided inhibitor optimization, while in vivo knockout and inhibitor studies (N-0385) confirmed TMPRSS2 is essential for SARS-CoV-2 replication in mouse airways across multiple variants including Omicron.

    Evidence X-ray crystallography at 1.95 Å, in vitro enzymatic assays, TMPRSS2-KO mice with Beta/Omicron infection, K18-hACE2 mouse model with N-0385

    PMID:35344983 PMID:35676539 PMID:36243815

    Open questions at the time
    • No human clinical trial data for TMPRSS2-specific inhibitors
    • Whether compensatory proteases emerge under TMPRSS2 blockade in vivo not addressed
  14. 2022 High

    Demonstrating that SARS-CoV-2 Omicron shifts away from TMPRSS2-dependent plasma membrane entry toward cathepsin-dependent endosomal entry explained its altered cell tropism and reduced pathogenicity in the lower respiratory tract.

    Evidence Pseudovirus entry in cells with differential TMPRSS2, gene deletion, drug inhibitors, airway organoids

    PMID:35104837

    Open questions at the time
    • Whether tropism shift is solely due to spike S1/S2 cleavage efficiency or involves other determinants
    • Long-term evolutionary trajectory of TMPRSS2 dependence unknown
  15. 2023 High

    The discovery that TMPRSS2 functions as a bona fide entry receptor for HCoV-HKU1—binding the viral RBD with high affinity even when catalytically dead—fundamentally expanded TMPRSS2's role from protease to receptor, revealing a dual protease-receptor function.

    Evidence Pseudovirus and authentic HKU1 infection, catalytic-dead TMPRSS2 mutants, Kd measurements, nanobody inhibition, primary bronchial cell infection

    PMID:37879362

    Open questions at the time
    • Whether other TTSPs can substitute as HKU1 receptors not tested
    • Structural basis not yet resolved at this point
  16. 2024 High

    Crystal and cryo-EM structures of HKU1 RBD–TMPRSS2 complexes revealed that HKU1 recognizes the TMPRSS2 catalytic groove through an insertion subdomain, that zymogen-to-active conformational changes dramatically increase binding affinity, and that sialoglycan binding to HKU1 NTD allosterically promotes RBD opening for TMPRSS2 engagement—providing a complete structural model of synergistic dual-receptor usage.

    Evidence Crystal structures of HKU1-RBD:TMPRSS2 and zymogen/active TMPRSS2 with nanobody, cryo-EM of HKU1 spike in multiple states, mutagenesis, cross-species tropism analysis

    PMID:38964326 PMID:38964329

    Open questions at the time
    • Whether therapeutic antibodies blocking the HKU1–TMPRSS2 interface are viable not tested
    • Structural basis for TMPRSS2's catalytic cleavage of HKU1 spike not resolved separately from receptor binding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full endogenous substrate repertoire of TMPRSS2 in normal physiology, whether TMPRSS2 inhibition is clinically effective against respiratory viral infections in humans, and the structural determinants governing selectivity between TMPRSS2's protease versus receptor functions for different viruses.
  • No endogenous physiological substrate comprehensively validated in vivo
  • No completed human clinical trial demonstrating efficacy of TMPRSS2-specific inhibitors
  • Mechanism by which TMPRSS2 loss is tolerated in knockout mice (no overt phenotype) unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0001618 virus receptor activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
ACE2ERGEZH2FOXO1HAI-2SERPINA1SMARCA4

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 SARS-CoV-2 uses ACE2 as its entry receptor and TMPRSS2 as the host serine protease required for priming (proteolytic activation) of the viral spike protein, enabling membrane fusion and cell entry; a clinically approved TMPRSS2 inhibitor (camostat) blocked this entry. Pseudovirus entry assays, live virus infection of cell lines with and without TMPRSS2 expression, pharmacological inhibition with camostat mesylate Cell High 32142651
2005 Recurrent chromosomal rearrangements fuse the 5' UTR/promoter of the androgen-regulated TMPRSS2 gene to ETS transcription factor coding sequences (ERG, ETV1), placing ETS oncogene expression under androgen-responsive TMPRSS2 promoter control in prostate cancer. Bioinformatics outlier expression analysis, RT-PCR, FISH on prostate cancer tissue samples, cell line experiments demonstrating androgen-responsive promoter driving ETS expression Science High 16254181
1999 TMPRSS2 is a transmembrane serine protease with androgen-regulated expression predominantly in prostate epithelium; its gene is located on chromosome 21 and encodes domains including a transmembrane region and serine protease domain, placing it on the cell surface. cDNA microarray profiling of androgen-treated prostate cancer cells, Northern analysis, in situ hybridization of normal and malignant prostate tissues Cancer research High 10485450
2008 The TMPRSS2-ERG gene fusion product drives invasion of prostate epithelial cells by engaging the plasminogen activation pathway, and ERG knockdown in TMPRSS2-ERG-positive VCaP cells inhibits invasion and induces a prostate differentiation transcriptional program. Transgenic mouse model (ERG under androgen-regulated promoter), introduction of ERG fusion into primary/immortalized prostate epithelial cells, ERG siRNA knockdown in VCaP cells, transcriptional profiling, invasion assays Neoplasia High 18283340
2022 The crystal structure of TMPRSS2 (1.95 Å) co-crystallized with nafamostat reveals the substrate binding pocket architecture; TMPRSS2 cleaves SARS-CoV-2 spike protein at multiple sites including the canonical S1/S2 cleavage site, and inhibitor potency was ranked using in vitro protease activity assays. Recombinant protein production, X-ray crystallography, in vitro protease activity assays, inhibitor IC50 determination Nature chemical biology High 35676539
2022 SARS-CoV-2 Omicron spike is less efficiently cleaved at S1/S2 compared to Delta, leading to reduced use of the TMPRSS2-dependent plasma membrane fusion pathway and greater reliance on the endocytic/cathepsin pathway; deletion of TMPRSS2 impaired Delta entry more than Omicron entry, explaining altered cell tropism. Spike-pseudotyped virus entry assays in cell lines with differential TMPRSS2 expression, TMPRSS2 gene deletion, drug inhibitors targeting specific entry pathways, syncytium formation assays, viral replication in human airway organoids Nature High 35104837
2018 The TMPRSS2-ERG fusion protein (ERG) interacts with mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complexes; ERG drives genome-wide retargeting of BAF complexes in an ETS DNA motif-dependent manner, and requires intact BAF complexes for chromatin occupancy and BAF ATPase activity for target gene regulation. Co-immunoprecipitation, ChIP-seq, prostate organoid model with BAF complex perturbation, genome-wide chromatin occupancy mapping Molecular cell High 30078722
2021 TMPRSS2 is identified as a direct substrate/binding partner of HAI-2 (hepatocyte growth factor activator inhibitor-2), which co-immunoprecipitates with and inhibits TMPRSS2 proteolytic activity; HAI-2 suppresses TMPRSS2-mediated pro-HGF activation, extracellular matrix degradation, and prostate cancer cell invasion and metastasis. Co-immunoprecipitation, LC/MS/MS, recombinant protein binding and inhibition assays, immunofluorescence colocalization, in vitro invasion assays, orthotopic xenograft mouse model Oncogene High 32778768
2013 Androgen regulation of TMPRSS2 requires an enhancer 13 kb upstream of the transcription start site containing an androgen response element (ARE) adjacent to two GATA2 binding sites; both the ARE and GATA2 sites contribute to enhancer activity, and a SNP (rs8134378) within the ARE reduces androgen receptor binding and transactivation. Bacterial artificial chromosome reporter assays, DNase I footprinting to identify GATA2 binding sites, ARE mutagenesis, androgen receptor binding assays, SNP functional analysis Molecular endocrinology High 24109594
2021 Alpha-1 antitrypsin (α1AT), a serine protease inhibitor abundant in the respiratory tract, binds and inactivates TMPRSS2, thereby inhibiting SARS-CoV-2 spike-mediated entry and viral replication in cell lines and primary human airway epithelial cultures. Bronchoalveolar lavage peptide/protein library screen, enzyme activity assays demonstrating α1AT inhibition of TMPRSS2, pseudovirus and authentic SARS-CoV-2 infection assays, primary human airway epithelial cultures Nature communications High 33741941
2017 Clinical isolates of human coronaviruses HCoV-OC43 and HCoV-HKU1 preferentially use cell-surface TMPRSS2 for spike protein priming and cell entry rather than endosomal cathepsins; cell-culture-adapted HCoV-OC43 lost ability to infect human bronchial tracheal epithelial air-liquid interface cultures. Viral infection assays with clinical isolates vs. cell-culture-adapted strains, pharmacological inhibition of TMPRSS2 vs. cathepsins, air-liquid interface culture infection Virology High 29217279
2023 TMPRSS2 functions as a proteinaceous entry receptor for human coronavirus HKU1: TMPRSS2 triggers HKU1 spike-mediated cell-cell fusion and pseudovirus infection; catalytically inactive TMPRSS2 mutants still support pseudovirus entry despite lacking spike cleavage activity; TMPRSS2 binds HKU1 receptor binding domain with high affinity (Kd ~137–334 nM) but does not bind SARS-CoV-2. Pseudovirus infection assays, cell-cell fusion assays, catalytically inactive TMPRSS2 mutants, binding affinity measurements, nanobody inhibition of TMPRSS2-HKU1 interaction, authentic HKU1 virus infection of primary human bronchial cells Nature High 37879362
2024 Crystal structure of the HKU1 receptor binding domain in complex with TMPRSS2 shows HKU1 recognizes residues lining the TMPRSS2 catalytic groove; positions 417 and 469 are determinants of HKU1 host tropism; structural basis of TMPRSS2 zymogen activation reveals autolytic conformational change that alters loops recognized by HKU1 and dramatically increases binding affinity. Crystal structure determination of HKU1-RBD:TMPRSS2 complex, zymogen and activated TMPRSS2 structures with nanobody, mutagenesis of interface residues, cross-species tropism analysis Cell High 38964326
2024 Cryo-EM structure of HKU1 spike bound to TMPRSS2 reveals that sialoglycan binding induces a conformational change in the NTD that promotes neighboring RBD opening for TMPRSS2 recognition, demonstrating synergistic glycan-protein receptor usage; the HKU1 RBD features an insertion subdomain engaging TMPRSS2 through three novel interfaces. Cryo-EM structure determination of HKU1 spike in inactive, glycan-activated, and TMPRSS2-anchored states, mutagenesis, binding assays Cell High 38964329
2021 TMPRSS2 directly interacts with ACE2 (demonstrated by endogenous co-immunoprecipitation in human cells), and ACE2 is a TMPRSS2 substrate; camostat (a TMPRSS2 inhibitor) blocked cleavage of pseudotype SARS-CoV-2 spike without disrupting TMPRSS2-ACE2 interaction; androgen deprivation reduced both TMPRSS2 and ACE2 expression, attenuating SARS-CoV-2 spike-mediated cellular entry. Co-immunoprecipitation of endogenous TMPRSS2 and ACE2, substrate cleavage assay, pseudotype SARS-CoV-2 entry assay with camostat, androgen receptor antagonist treatment iScience Medium 33681723
2022 Furin and TMPRSS2 act synergistically in SARS-CoV-2 infectivity: the S2' fusion activation site (KPS815↓) was identified by proteomics and its cleavage enhanced by ACE2 engagement; ACE2 shedding by TMPRSS2 is required for TMPRSS2-mediated enhancement of cell-to-cell fusion in the absence of S1/S2 priming; the ACE2 collectrin dimerization domain is essential for the TMPRSS2 effect on fusion. Proteomics identification of S2' cleavage site, cell-to-cell fusion assays, pharmacological inhibitors of furin (BOS) and TMPRSS2 (camostat), ACE2 domain mutant constructs, authentic SARS-CoV-2 infection of Calu-3 cells Journal of virology High 35343766
2021 TMPRSS2-mediated entry into lung cells is the dominant pathway for SARS-CoV-2, while hydroxychloroquine efficiently blocks cathepsin L-dependent endosomal entry but not TMPRSS2-dependent plasma membrane entry; SARS-CoV-2 is more dependent on TMPRSS2 than SARS-CoV-1, and this difference is determined by the furin cleavage site in the SARS-CoV-2 spike. Pseudovirus entry assays in cells with varying TMPRSS2 expression, pharmacological inhibition of cathepsin L vs. TMPRSS2, furin-cleavage site ablation and transfer mutagenesis between SARS-CoV-1 and -2 spikes PLoS pathogens High 33465165
2022 TMPRSS2 is essential for SARS-CoV-2 Beta and Omicron replication in mouse airways in vivo; TMPRSS2-knockout mice show strongly reduced viral replication in nose, trachea, and lung for Beta variant and reduced Omicron spread despite Omicron preferring cathepsins in vitro. TMPRSS2-knockout C57BL/6 mice infected with SARS-CoV-2 Beta and Omicron variants, measurement of viral titers in respiratory tract tissues, weight loss monitoring Nature communications High 36243815
2022 A small-molecule compound N-0385 inhibits TMPRSS2 with low nanomolar potency and blocks SARS-CoV-2 infection in human lung cells and colonoids; in the K18-hACE2 transgenic mouse model, N-0385 provides prophylactic and therapeutic benefit, confirming TTSP-mediated spike proteolytic maturation is critical for SARS-CoV-2 infection in vivo. In vitro TMPRSS2 inhibition assays, Calu-3 and colonoid infection assays, K18-hACE2 transgenic mouse model prophylaxis and treatment experiments Nature High 35344983
2015 TMPRSS2 protease activity at the cell surface activates hepatitis C virus (HCV) infection at the post-binding/entry stage; TMPRSS2 wild-type but not catalytically inactive mutant enhances HCV susceptibility in Huh7 cells, and TMPRSS2 knockdown reduces infection. Stable TMPRSS2 wild-type and catalytic mutant expression in Huh7 cells, HCV infection assays, siRNA knockdown, cell-surface protease activity assays Hepatology High 25203900
2015 TMPRSS2 isoform 1 (with extended N-terminal cytoplasmic domain) is expressed in lung-derived cell lines and tissues, colocalizes with influenza hemagglutinin (HA), cleaves and activates HA, and activates SARS-CoV spike protein for cathepsin L-independent cell entry. RT-PCR for isoform expression, colocalization imaging, functional cleavage assays, pseudovirus entry assays with cathepsin inhibition PloS one Medium 26379044
2021 EZH2 methylates ERG (the TMPRSS2-ERG fusion product) at lysine K362 within the internal auto-inhibitory domain; K362 methylation modifies intra-domain interactions, favors DNA binding, and enhances ERG transcriptional activity; AKT-phosphorylated EZH2 (pS21) favors ERG methylation downstream of PTEN loss; ERG and EZH2 interact and co-occupy genomic sites forming trans-activating complexes. In vitro methylation assays, mutagenesis of K362, ChIP-seq, Co-immunoprecipitation, genetically engineered mouse model (ERG/PTEN), mass spectrometry Nature communications High 34230470
2010 Androgen treatment can induce the TMPRSS2:ERG chromosomal fusion in both malignant and non-malignant prostate epithelial cells, associated with androgen-induced spatial gene proximity of TMPRSS2 and ERG loci and expression of PIWIL1; this demonstrates fusions can arise prior to malignant transformation. RT-PCR detection of fusion transcripts after androgen treatment, FISH for gene proximity measurement, androgen receptor CAG repeat length analysis Cancer research Medium 20947519
2017 FOXO1 binds ERG (the TMPRSS2-ERG fusion product) and inhibits its transcriptional activity independently of FOXO1's own transcriptional activity; FOXO1 knockdown increases VCaP cell invasion in an ERG-dependent manner; concomitant ERG transgene expression and Foxo1 deletion in mouse prostate causes high-grade prostatic intraepithelial neoplasia. Co-immunoprecipitation of FOXO1 and ERG, transcriptional reporter assays, siRNA knockdown, invasion assays, genetically engineered mouse model Cancer research High 28986382
2019 Androgen receptor-activated enhancers E1 and E2 (located between PRCAT38 and TMPRSS2 on chromosome 21) form chromatin loops with both the PRCAT38 and TMPRSS2 promoters, co-regulating both genes; enhancer activity is mediated by AR/FOXA1 binding and acetyltransferase p300; knockout of E1 or E2 simultaneously reduced transcription of both genes and inhibited cell growth and migration. Chromatin looping assays (3C/ChIA-PET), enhancer knockout (CRISPR), ChIP for AR, FOXA1, and p300, cell growth and migration assays Cells Medium 31405024
2022 A common TMPRSS2 variant rs12329760 (p.V160M) reduces TMPRSS2 catalytic activity and is less able to support SARS-CoV-2 spike-mediated entry into cells; homozygous carriers have significantly decreased risk of severe COVID-19. SARS-CoV-2 pseudovirus entry assay in HEK293 cells co-transfected with ACE2 and wild-type or V160M TMPRSS2, epidemiological association in 2,244 ICU patients Current research in translational medicine Medium 35104687
2022 An RNA G-quadruplex (RG4) structure within TMPRSS2 mRNA inhibits TMPRSS2 translation; G4-specific stabilizers attenuate SARS-CoV-2 infection in pseudovirus systems and mouse models; TMPRSS2 protein is increased in COVID-19 patient lungs. Bioinformatics identification of RG4, biochemical and biophysical RG4 characterization, in vitro translation assays, pseudovirus infection, mouse model with G4 stabilizers, COVID-19 patient lung protein analysis Nature communications Medium 35301316
2022 Antithrombin (AT), an endogenous serine protease inhibitor, binds and inhibits TMPRSS2 (demonstrated by molecular docking and enzyme activity assays), blocking spike-mediated entry of multiple coronaviruses and suppressing authentic SARS-CoV-2 lung cell infection; heparin/fondaparinux activation of AT increases its anti-TMPRSS2 activity. Molecular docking, enzyme activity assays, pseudovirus entry assays for multiple coronavirus spikes, authentic SARS-CoV-2 lung cell infection assay Journal of medical virology Medium 36056630
2020 miR-98-5p directly targets TMPRSS2 mRNA and was mechanistically validated as a regulator of TMPRSS2 protein expression in human lung and umbilical vein endothelial cells. Bioinformatic miRNA target prediction, functional validation of miR-98-5p regulation of TMPRSS2 in two human endothelial cell lines Biomedicines Low 33143053
2021 Androgens regulate TMPRSS2 expression in lung epithelial cells via androgen receptor; antiandrogen enzalutamide reduces TMPRSS2 levels in human lung cells and mouse lung, significantly reducing SARS-CoV-2 entry and infection. Quantitative gene expression analysis in lung cell lines and mouse lung, antiandrogen treatment, SARS-CoV-2 infection assays in lung cells with and without enzalutamide Nature communications Medium 34210968
2023 PM2.5 activates AhR, which translocates to the nucleus and directly binds the TMPRSS2 promoter, upregulating TMPRSS2 and downstream IL18 expression to promote lung cancer progression; TMPRSS2 depletion suppressed anchorage-independent growth and xenograft tumor growth. AhR nuclear translocation assays, ChIP showing AhR binding to TMPRSS2 promoter, TMPRSS2 knockdown in lung cancer cells, anchorage-independent growth assays, xenograft mouse model EMBO molecular medicine Medium 36975376
2013 TMPRSS2/ERG gene fusion is expressed in prostate cancer stem cells with monoallelic regulation; TMPRSS2 transcription is subject to tight monoallelic control throughout the prostate epithelial hierarchy in both normal and tumor tissues, relaxed during differentiation. FISH for fusion gene in sorted prostate cancer stem cells, allele-specific expression analysis, single cell clonal analysis of asymmetric division Nature communications Medium 23535644

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 14282 32142651
2005 Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science (New York, N.Y.) 3117 16254181
2022 Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature 842 35104837
2020 SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. The EMBO journal 818 32246845
2008 Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia (New York, N.Y.) 561 18283340
1999 Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer research 426 10485450
2020 TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention? Cancer discovery 291 32276929
2020 ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. The ocular surface 270 32544566
2020 Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells. The Journal of allergy and clinical immunology 264 32422146
2007 Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 228 17334343
2008 Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer research 211 18172298
2020 ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. Frontiers in immunology 210 33117379
2017 TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 210 28778717
2020 ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 187 32861070
2021 Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2. PLoS pathogens 176 33465165
2022 A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature 170 35344983
2017 Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 169 29217279
2022 Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation. Nature chemical biology 158 35676539
2020 Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Proceedings of the National Academy of Sciences of the United States of America 144 33310900
2022 Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity. Journal of virology 140 35343766
2001 Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. The Journal of pathology 135 11169526
2010 Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 130 20118910
2020 Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. Journal of biomolecular structure & dynamics 116 32469279
2020 miR-98 Regulates TMPRSS2 Expression in Human Endothelial Cells: Key Implications for COVID-19. Biomedicines 116 33143053
2020 Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS computational biology 116 33290397
2021 Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection. Nature communications 112 33741941
2013 Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element. Molecular endocrinology (Baltimore, Md.) 106 24109594
2012 Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. The Journal of urology 105 22245323
2021 Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. The Journal of clinical investigation 101 33180746
2014 TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. PloS one 100 24505269
2018 Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Molecular cell 86 30078722
2020 Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat. Chemical science 85 35382133
2010 TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Human pathology 85 21040948
2021 Contributions of human ACE2 and TMPRSS2 in determining host-pathogen interaction of COVID-19. Journal of genetics 84 33707363
2017 Significance of the TMPRSS2:ERG gene fusion in prostate cancer. Molecular medicine reports 84 28849022
2010 Androgen-induced TMPRSS2:ERG fusion in nonmalignant prostate epithelial cells. Cancer research 84 20947519
2022 Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways. Nature communications 82 36243815
2020 Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2. PloS one 82 32726325
2020 Gene of the month: TMPRSS2 (transmembrane serine protease 2). Journal of clinical pathology 81 32873700
2023 TMPRSS2 is a functional receptor for human coronavirus HKU1. Nature 80 37879362
2021 Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes. Scientific reports 80 34045511
2021 Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19. iScience 79 33681723
2020 Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2. Journal of medical virology 79 32441816
2020 ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease. Microbial pathogenesis 76 33278516
2020 ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain. Journal of medical virology 72 32691890
2022 RNA G-quadruplex in TMPRSS2 reduces SARS-CoV-2 infection. Nature communications 67 35301316
2023 PM2.5 promotes lung cancer progression through activation of the AhR-TMPRSS2-IL18 pathway. EMBO molecular medicine 65 36975376
2021 The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells. Nature communications 63 34210968
2018 TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 63 29844131
2020 Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents. Biochemical and biophysical research communications 58 32703421
2022 The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment. International journal of molecular sciences 57 35163273
2017 Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion. Cancer research 53 28986382
2014 TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene 52 25263440
2023 TMPRSS2 Is Essential for SARS-CoV-2 Beta and Omicron Infection. Viruses 51 36851486
2021 Term Human Placental Trophoblasts Express SARS-CoV-2 Entry Factors ACE2, TMPRSS2, and Furin. mSphere 49 33853873
2021 Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung. Environmental research 48 33422505
2010 TMPRSS2-ERG gene fusion and clinicopathologic characteristics of Korean prostate cancer patients. Urology 45 20800881
2013 Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells. Nature communications 44 23535644
2022 A common TMPRSS2 variant has a protective effect against severe COVID-19. Current research in translational medicine 43 35104687
2015 Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection. Hepatology (Baltimore, Md.) 43 25203900
2021 Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells. Molecular therapy. Nucleic acids 41 34692233
2021 Initial study on TMPRSS2 p.Val160Met genetic variant in COVID-19 patients. Human genomics 40 34001248
2020 Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis. Oncogene 40 32778768
2021 Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. Stem cells translational medicine 39 33188579
2021 Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19. Particle and fibre toxicology 39 33706759
2021 EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer. Nature communications 37 34230470
2019 Androgen Receptor-Activated Enhancers Simultaneously Regulate Oncogene TMPRSS2 and lncRNA PRCAT38 in Prostate Cancer. Cells 37 31405024
2024 Human coronavirus HKU1 recognition of the TMPRSS2 host receptor. Cell 34 38964328
2020 Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 and TMPRSS2 in the Respiratory Tract. Viruses 34 33081421
2020 ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients. Cell transplantation 32 33108902
2015 TMPRSS2 Isoform 1 Activates Respiratory Viruses and Is Expressed in Viral Target Cells. PloS one 32 26379044
2021 ACE2 and TMPRSS2 in human saliva can adsorb to the oral mucosal epithelium. Journal of anatomy 31 34590312
2011 The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers. Human pathology 31 21937078
2021 A variant in TMPRSS2 is associated with decreased disease severity in COVID-19. Meta gene 30 34075330
2016 PCA3 and TMPRSS2-ERG gene fusions as diagnostic biomarkers for prostate cancer. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 29 27041928
2024 TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry. Cell 28 38964329
2022 ACE2 and TMPRSS2 SNPs as Determinants of Susceptibility to, and Severity of, a COVID-19 Infection. British journal of biomedical science 26 35996506
2021 Prostate adenocarcinoma and COVID-19: The possible impacts of TMPRSS2 expressions in susceptibility to SARS-CoV-2. Journal of cellular and molecular medicine 26 33609069
2021 Computational analysis of TMPRSS2 expression in normal and SARS-CoV-2-infected human tissues. Chemico-biological interactions 26 34284028
2020 TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients. Journal of experimental & clinical cancer research : CR 26 32967703
2020 Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2. bioRxiv : the preprint server for biology 26 33083800
2023 TMPRSS2 polymorphism (rs12329760) and the severity of the COVID-19 in Iranian population. PloS one 25 36795725
2022 Genetic association of TMPRSS2 rs2070788 polymorphism with COVID-19 case fatality rate among Indian populations. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 25 34995811
2021 Spiking dependence of SARS-CoV-2 pathogenicity on TMPRSS2. Journal of medical virology 25 33638460
2021 Age and gender differences in ACE2 and TMPRSS2 expressions in oral epithelial cells. Journal of translational medicine 25 34412632
2019 Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer. The Prostate 25 31614005
2022 Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review. European journal of medical research 24 35193695
2021 Pulmonary, cardiac and renal distribution of ACE2, furin, TMPRSS2 and ADAM17 in rats with heart failure: Potential implication for COVID-19 disease. Journal of cellular and molecular medicine 24 33660945
2020 Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19? Phytomedicine : international journal of phytotherapy and phytopharmacology 23 33380375
2011 Role of TMPRSS2-ERG gene fusion in negative regulation of PSMA expression. PloS one 23 21731703
2024 Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus. Cell 21 38964326
2022 The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19. Expert opinion on drug discovery 21 35072549
2022 Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection. Journal of medical virology 20 36056630
2017 Height, Obesity, and the Risk of TMPRSS2:ERG-Defined Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20 29167279
2022 ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19. Oral diseases 19 35000261
2022 Distinct spatial arrangements of ACE2 and TMPRSS2 expression in Syrian hamster lung lobes dictates SARS-CoV-2 infection patterns. PLoS pathogens 19 35255100
2022 Association of the Transmembrane Serine Protease-2 (TMPRSS2) Polymorphisms with COVID-19. Viruses 19 36146782
2020 Genetic Susceptibility of ACE2 and TMPRSS2 in Six Common Cancers and Possible Impacts on COVID-19. Cancer research and treatment 19 33421977
2022 Estradiol reduces ACE2 and TMPRSS2 mRNA levels in A549 human lung epithelial cells. Drug development research 18 35103351
2022 Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection in cell culture. Communications biology 17 35804152