Affinage

TMPRSS2

Transmembrane protease serine 2 · UniProt O15393

Length
492 aa
Mass
53.9 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMPRSS2 is an androgen-regulated, cell-surface type II transmembrane serine protease that is produced as a zymogen and undergoes autocatalytic maturation, with its substrate-binding pocket explaining the specificity of clinical inhibitors (PMID:10485450, PMID:35676539). Its best-characterized role is in respiratory and enteric virus entry: TMPRSS2 primes the spike protein of SARS-CoV-2 by cleaving at the S1/S2 and S2' (KPS815↓) sites, enabling rapid, pH-independent fusion at the plasma membrane and bypassing the slower endosomal cathepsin L pathway, with the two entry routes being mutually exclusive (PMID:32142651, PMID:34159616, PMID:35343766). This priming function extends across coronaviruses (HCoV-OC43, HKU1) and is required in vivo, as TMPRSS2-knockout mice show strongly reduced replication of multiple SARS-CoV-2 variants even when those variants favor the cathepsin pathway in culture (PMID:36851486, PMID:36243815, PMID:29217279, PMID:35344983). For HKU1, TMPRSS2 additionally serves as a direct proteinaceous receptor: the HKU1 receptor-binding domain engages the TMPRSS2 catalytic groove through an insertion subdomain, sialoglycan binding promotes RBD opening, and autocatalytic activation increases receptor affinity, while catalytically dead TMPRSS2 still functions as a receptor (PMID:37879362, PMID:38964329, PMID:38964326). TMPRSS2 is inhibited by the cognate inhibitor HAI-2 and by circulating serpins α1-antitrypsin and antithrombin, all of which block its proteolytic activity and viral entry (PMID:33741941, PMID:32778768, PMID:36056630). Independently, the androgen-responsive TMPRSS2 promoter drives recurrent fusion with ETS oncogenes (ERG, ETV1) in prostate cancer; the TMPRSS2-ERG oncoprotein retargets BAF (SWI/SNF) chromatin-remodeling complexes, activates NO-cGMP-PKG signaling, blocks neuroendocrine and luminal differentiation, and is destabilized by GSK3β/WEE1-driven dual phosphorylation and FBW7-mediated proteasomal degradation (PMID:16254181, PMID:32871104, PMID:30078722, PMID:30718921, PMID:25263440). TMPRSS2 is also a receptor for Paeniclostridium sordellii hemorrhagic toxin TcsH (PMID:35882856).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Established TMPRSS2 as a cell-surface serine protease whose expression is androgen-driven in prostate epithelium, defining the regulatory wiring later exploited by oncogenic fusions.

    Evidence cDNA microarray, Northern blot, and in situ hybridization in prostate epithelial cells

    PMID:10485450

    Open questions at the time
    • Did not identify physiological substrates
    • No mechanism for how androgen signaling reaches the gene
  2. 2001 Medium

    Mapped TMPRSS2 tissue distribution to GI, urogenital, and respiratory epithelia and to prostate luminal cells, establishing the anatomical contexts relevant to both cancer and later viral entry roles.

    Evidence cDNA cloning, Northern blot, in situ hybridization in mouse and human tissues

    PMID:11169526

    Open questions at the time
    • Functional consequence of broad epithelial expression unaddressed
    • No protease activity data
  3. 2005 High

    Showed that the androgen-responsive TMPRSS2 promoter fuses to ETS oncogenes (ERG, ETV1) to drive their overexpression, defining the founding oncogenic mechanism of TMPRSS2 in prostate cancer.

    Evidence Outlier expression bioinformatics, FISH, RT-PCR, and cell line experiments in prostate tumors

    PMID:16254181

    Open questions at the time
    • Did not establish downstream effector pathways of the fusion oncoprotein
    • Mechanism of rearrangement formation unknown
  4. 2017 Medium

    Demonstrated that clinical coronavirus isolates prefer cell-surface TMPRSS2 over endosomal cathepsins, foreshadowing TMPRSS2 as a general coronavirus entry factor.

    Evidence Pathway-inhibitor infection assays comparing clinical vs. culture-adapted strains in human airway cultures

    PMID:29217279

    Open questions at the time
    • Direct cleavage of spike not biochemically resolved here
    • Single-lab pharmacological dissection
  5. 2018 High

    Resolved how the TMPRSS2-ERG oncoprotein reprograms chromatin and cell fate, showing it retargets BAF complexes and blocks differentiation, explaining its oncogenic output.

    Evidence Co-IP, ERG/BAF ChIP-seq, BAF depletion, and prostate organoid basal-to-luminal transition assays; plus ERG-driven repression of NE/luminal programs

    PMID:25263440 PMID:30078722

    Open questions at the time
    • How fusion alters BAF assembly stoichiometry unresolved
    • Relationship between chromatin retargeting and clinical progression incomplete
  6. 2019 Medium

    Identified the AR/FOXA1-driven enhancers and downstream NO-cGMP-PKG signaling axis activated by TMPRSS2-ERG, linking enhancer biology to a druggable oncogenic effector pathway.

    Evidence ChIP-seq, chromatin looping, CRISPR enhancer knockout; sGC subunit ChIP-seq, cGMP/PKG assays, and xenograft sGC inhibition

    PMID:30718921 PMID:31405024

    Open questions at the time
    • Single-lab mechanistic studies
    • Generalizability across fusion-positive tumor subtypes untested
  7. 2020 High

    Defined TMPRSS2 as the spike-priming protease enabling SARS-CoV-2 entry alongside ACE2, immediately establishing it as an antiviral target.

    Evidence Pseudovirus and authentic virus entry assays with camostat mesylate inhibition; plus enteroid infection showing TMPRSS2/TMPRSS4 fusogenic facilitation

    PMID:32142651 PMID:32404436

    Open questions at the time
    • Cleavage sites and catalytic mechanism not yet structurally defined
    • Relative contribution of TMPRSS2 vs other proteases in vivo unresolved
  8. 2020 High

    Identified HAI-2 as the cognate endogenous inhibitor of TMPRSS2, linking protease regulation to substrate (pro-HGF) activation and prostate cancer metastasis.

    Evidence Co-IP/LC-MS/MS, recombinant inhibition assays, co-localization, pro-HGF/ECM degradation assays, and orthotopic xenograft metastasis model

    PMID:32778768

    Open questions at the time
    • Physiological substrate repertoire beyond pro-HGF incompletely defined
    • Regulation of HAI-2/TMPRSS2 stoichiometry in tissue unknown
  9. 2020 High

    Established the degradation logic of the TMPRSS2-ERG oncoprotein, showing DNA-damage-induced GSK3β/WEE1 dual phosphorylation drives FBW7-mediated proteasomal turnover, a determinant of chemotherapy response.

    Evidence Phosphosite mutagenesis, kinase knockdown/inhibition, FBW7 co-IP, proteasome inhibition, and xenograft chemoresistance experiments

    PMID:32871104

    Open questions at the time
    • Non-canonical degron recognition mechanism not structurally defined
    • Role of PTEN-loss escape in patients incomplete
  10. 2021 High

    Resolved that TMPRSS2 abundance dictates which entry pathway SARS-CoV-2 uses, showing the plasma-membrane and endosomal routes are mutually exclusive and kinetically distinct.

    Evidence Live-cell imaging of entry kinetics with reciprocal gain/loss of function and pathway-selective inhibitors

    PMID:34159616

    Open questions at the time
    • Determinants of pathway choice in heterogeneous tissues unaddressed
    • Quantitative threshold of TMPRSS2 needed for plasma-membrane entry undefined
  11. 2021 Medium

    Connected TMPRSS2 to host restriction and innate immunity, showing TMPRSS2-routed plasma-membrane entry evades NCOA7 restriction and that α1-antitrypsin inactivates TMPRSS2 to block infection.

    Evidence NCOA7 over/knockout with furin-site mutagenesis; plus BAL protein-library screen, enzymatic inhibition, and primary airway viral replication assays

    PMID:33741941 PMID:34807954

    Open questions at the time
    • Single-lab studies
    • In vivo relevance of α1AT/NCOA7 axis to disease severity unestablished
  12. 2022 High

    Provided the atomic structure and maturation mechanism of TMPRSS2, defining zymogen autocatalytic activation, S1/S2 cleavage, and the basis of inhibitor specificity.

    Evidence Recombinant protein, enzymatic assays, 1.95 Å co-crystal with nafamostat, and IC50 ranking of clinical inhibitors

    PMID:35676539

    Open questions at the time
    • Structure of the full-length membrane-anchored protease not resolved
    • Conformational dynamics of activation captured only statically
  13. 2022 High

    Established TMPRSS2 dependence in vivo and variant-specific usage, showing knockout mice are protected across variants and that Omicron's reduced S1/S2 cleavage shifts it toward the cathepsin pathway in vitro yet retains in vivo TMPRSS2 dependence.

    Evidence TMPRSS2-KO mouse infection with Beta/Gamma/Omicron, viral titers, plus pseudovirus, spike cleavage, and syncytium assays

    PMID:35104837 PMID:36243815 PMID:36851486

    Open questions at the time
    • Mechanism reconciling in vitro vs in vivo pathway preference incomplete
    • Cell types responsible for in vivo TMPRSS2 dependence not pinpointed
  14. 2022 High

    Dissected the furin/TMPRSS2 synergy and identified the S2' cleavage site, showing ACE2 engagement (via its collectrin domain) and TMPRSS2-mediated ACE2 shedding enhance fusion.

    Evidence Proteomics S2' site mapping, furin and TMPRSS2 inhibitors, ACE2 domain deletions, and quantitative cell-cell fusion assays

    PMID:35343766

    Open questions at the time
    • Order and coupling of furin, TMPRSS2, and ACE2 events not fully sequenced
    • Single-lab system
  15. 2022 High

    Validated TMPRSS2 as a therapeutic target in vivo and expanded the inhibitor toolkit, including a low-nanomolar small molecule efficacious in mice and additional serpin, peptide, and peptidomimetic inhibitors.

    Evidence N-0385 efficacy in K18-hACE2 mice; plus antithrombin/heparin, lactoferricin, and catalytic-site peptidomimetic inhibition and viral infection assays

    PMID:35344983 PMID:35804152 PMID:36056630 PMID:36081512

    Open questions at the time
    • Several inhibitor studies are single-lab in vitro
    • Clinical translation and resistance not addressed
  16. 2022 Medium

    Linked TMPRSS2 levels to host genetics and transcriptional/translational control, identifying a hypomorphic protective variant, an IL-1β–p38–GATA2 induction axis, and an mRNA G-quadruplex that represses translation.

    Evidence V160M functional pseudovirus assay with GenOMICC cohort association; cytokine/p38/GATA2 manipulation; RG4 biochemistry, translation reporters, and G4-stabilizer mouse infection

    PMID:34950146 PMID:35104687 PMID:35301316

    Open questions at the time
    • Single-lab mechanistic studies
    • Causal contribution of each regulatory layer to clinical outcome uncertain
  17. 2023 High

    Revealed a non-protease function: TMPRSS2 acts as a direct proteinaceous receptor for HKU1, binding the viral RBD with high affinity independently of catalytic activity.

    Evidence Kd measurements, catalytically dead mutants, pseudovirus and authentic HKU1 infection of primary bronchial cells, and nanobody neutralization

    PMID:37879362

    Open questions at the time
    • Whether receptor and protease roles operate on the same molecules simultaneously unclear
    • Relevance to other coronaviruses untested
  18. 2024 High

    Provided the structural basis for TMPRSS2 receptor function, showing HKU1 RBD engages the catalytic groove through an insertion subdomain, that sialoglycan-induced RBD opening synergizes with protein recognition, and that autocatalytic activation increases binding affinity.

    Evidence Cryo-EM and X-ray structures of HKU1 RBD/TMPRSS2 and nanobody/zymogen complexes with interface mutagenesis and species comparison

    PMID:38964326 PMID:38964329

    Open questions at the time
    • Membrane-proximal architecture during fusion not resolved
    • Host-range determinants (residues 417/469) tested in limited species set
  19. 2022 High

    Extended TMPRSS2's receptor function beyond viruses, identifying it as a receptor for the bacterial toxin TcsH via genome-wide CRISPR screening.

    Evidence Two parallel CRISPR/Cas9 screens, TMPRSS2 deletion, CROPs-domain binding assays, and Tmprss2-/- mouse toxin challenge

    PMID:35882856

    Open questions at the time
    • Whether catalytic activity contributes to toxin entry unknown
    • Structural basis of TcsH-TMPRSS2 binding undefined
  20. 2023 Medium

    Implicated TMPRSS2 in environmental carcinogenesis outside the prostate, showing PM2.5-activated AhR transcriptionally upregulates TMPRSS2 to promote lung cancer growth.

    Evidence AhR ChIP at the TMPRSS2 promoter, TMPRSS2 knockdown, anchorage-independent growth, and xenograft assays

    PMID:36975376

    Open questions at the time
    • Single-lab study
    • Molecular role of TMPRSS2 protease activity in lung tumor growth undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous physiological substrates and normal-tissue function of TMPRSS2 (beyond pro-HGF) remain undefined, as does how its protease and receptor roles are coordinated.
  • Native substrate set unknown
  • Physiological loss-of-function phenotype uncharacterized
  • Coupling of receptor vs protease functions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0001618 virus receptor activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ACE2ANTITHROMBINBRD4ERGFBW7FOXO1HAI-2SERPINA1
Complex memberships
BAF (SWI/SNF) complex (via TMPRSS2-ERG)

Evidence

Reading pass · 36 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 for S protein priming; a clinically approved TMPRSS2 inhibitor (camostat mesylate) blocked viral entry into cells. Pseudovirus entry assay, authentic virus infection, pharmacological inhibition with camostat mesylate Cell High 32142651
1999 TMPRSS2 is a membrane-bound serine protease expressed on the cell surface; its expression in prostate epithelial cells is upregulated by androgens. cDNA microarray profiling, Northern analysis, in situ hybridization Cancer research High 10485450
2005 TMPRSS2 undergoes recurrent chromosomal rearrangements with ETS transcription factor genes ERG and ETV1 in prostate cancer; the androgen-responsive promoter elements of TMPRSS2 drive overexpression of the fusion ETS family members. Bioinformatics outlier expression analysis, FISH, RT-PCR, cell line experiments Science High 16254181
2022 Crystal structure of TMPRSS2 at 1.95 Å resolved in complex with the inhibitor nafamostat; TMPRSS2 is produced as a zymogen that undergoes autocatalytic maturation, cleaves SARS-CoV-2 spike protein at multiple sites including the S1/S2 site, and has a substrate-binding pocket with distinctive features that explain inhibitor specificity. Recombinant protein production, enzymatic activity assays, 1.95 Å X-ray co-crystal structure with nafamostat, IC50 measurements for clinical inhibitors Nature chemical biology High 35676539
2021 TMPRSS2 expression level determines the entry pathway of SARS-CoV-2: in TMPRSS2-expressing cells, virus enters rapidly (~10 min) at the plasma membrane in a pH-independent manner; in cells lacking TMPRSS2, virus is endocytosed and enters via acid-activated cathepsin L (~40–60 min post-infection). The two pathways are mutually exclusive. Live-cell imaging of viral entry kinetics, pharmacological inhibition of TMPRSS2 vs. cathepsin L, TMPRSS2 overexpression in non-expressing cells The EMBO journal High 34159616
2022 SARS-CoV-2 Omicron BA.1 spike is inefficiently cleaved at S1/S2 compared to Delta, and Omicron inefficiently uses TMPRSS2 for cell entry, shifting entry preference to the endocytic/cathepsin pathway; TMPRSS2 deletion affected Delta entry to a greater extent than Omicron, and syncytium formation by Omicron spike was substantially impaired consistent with defective TMPRSS2 usage. Pseudovirus entry assays, TMPRSS2 deletion experiments, drug inhibitor pathway studies, syncytium assays, spike cleavage analysis Nature High 35104837
2020 TMPRSS2 and TMPRSS4 facilitate SARS-CoV-2 spike fusogenic activity and promote viral entry into human small intestinal enterocytes; productive SARS-CoV-2 infection occurs in ACE2+ mature enterocytes in human small intestinal enteroids. Human small intestinal enteroid infection, spike fusogenicity assays, enterocyte infection experiments Science immunology High 32404436
2021 α1-antitrypsin (α1AT) binds and inactivates the serine protease TMPRSS2, thereby inhibiting SARS-CoV-2 spike-mediated entry and viral replication in cell lines and primary human airway epithelial cultures at physiological concentrations. Bronchoalveolar lavage peptide/protein library screen, TMPRSS2 enzymatic activity assay, viral replication assay in primary cells, binding assays Nature communications High 33741941
2023 TMPRSS2 functions as a proteinaceous receptor for the seasonal human coronavirus HKU1; TMPRSS2 binds the HKU1 receptor-binding domain with high affinity (Kd 334 and 137 nM for HKU1A and HKU1B), triggers HKU1 spike-mediated cell-cell fusion and pseudovirus infection; catalytically inactive TMPRSS2 mutants retain receptor function but cannot cleave HKU1 spike. Anti-TMPRSS2 nanobodies block HKU1 infection of primary human bronchial cells. Pseudovirus infection assays, cell-cell fusion assays, binding affinity measurements, catalytically inactive TMPRSS2 mutants, anti-TMPRSS2 nanobodies, authentic HKU1 virus infection of primary cells Nature High 37879362
2024 Cryo-EM structure of HKU1 RBD bound to human TMPRSS2 reveals that HKU1 RBD recognizes TMPRSS2 via an insertion subdomain through three distinct interfaces; sialoglycan binding induces a conformational change in the NTD that promotes RBD opening for TMPRSS2 recognition, demonstrating a synergistic glycan/protein receptor mechanism. Positions 417 and 469 in TMPRSS2 are determinants of HKU1 host tropism. Cryo-EM structure determination, mutagenesis, binding assays, pseudovirus infection assays Cell High 38964329
2024 Crystal structure of HKU1-CoV RBD in complex with TMPRSS2 shows HKU1 recognizes residues lining the TMPRSS2 catalytic groove; structure of a receptor-blocking nanobody with zymogen and activated TMPRSS2 provides the structural basis of TMPRSS2 autocatalytic activating conformational change, which dramatically increases binding affinity for HKU1. X-ray crystal structure of HKU1 RBD/TMPRSS2 complex and nanobody/TMPRSS2 complexes, mutagenesis of interface residues, species comparison Cell High 38964326
2022 TMPRSS2 is essential for SARS-CoV-2 Beta and Omicron infection in the murine airways; TMPRSS2 knockout mice showed strongly reduced replication of Beta variant in nose, trachea, and lung and were protected from weight loss and disease; Omicron infection was also significantly reduced in the upper and lower respiratory tract of TMPRSS2-KO mice despite Omicron preferring the cathepsin pathway in vitro. TMPRSS2-knockout mouse model, intranasal infection with Beta and Omicron variants, viral titer measurements in tissues, weight loss monitoring Viruses High 36851486
2022 Essential role of TMPRSS2 in SARS-CoV-2 infection of murine airways confirmed in vivo; Omicron replication is significantly reduced in TMPRSS2-knockout mice despite using the cathepsin pathway efficiently in vitro, demonstrating that in vivo TMPRSS2 dependency is not predicted by cell culture results alone. TMPRSS2-knockout mice, infection with multiple SARS-CoV-2 variants (Omicron, mouse-adapted QHmusX, Beta, Gamma), viral replication measurements in airways Nature communications High 36243815
2022 TMPRSS2 rs12329760 T allele (p.Val160Met substitution) reduces TMPRSS2 catalytic activity and is less able to support SARS-CoV-2 spike-mediated entry in vitro; the T allele is associated with reduced likelihood of severe COVID-19 in a large clinical cohort. HEK293 cell co-transfection with ACE2 and WT or V160M TMPRSS2, SARS-CoV-2 pseudovirus entry assay, logistic regression in 2,244 ICU patients (GenOMICC study) Current research in translational medicine Medium 35104687
2021 TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction: overexpression of TMPRSS2, which routes virus to plasma membrane fusion rather than endosomal entry, renders SARS-CoV-2 less sensitive to NCOA7-mediated restriction; removal of the furin cleavage site similarly reduced NCOA7 sensitivity. TMPRSS2 overexpression, NCOA7 ectopic expression and gene knockout, spike pseudovirus infection, furin cleavage site mutagenesis PLoS pathogens Medium 34807954
2021 Hydroxychloroquine blocks SARS-CoV-2 entry mediated by cathepsin L but not by TMPRSS2; SARS-CoV-2 entry is more dependent on TMPRSS2 than SARS-CoV-1 entry, a difference reversed by ablating the SARS-CoV-2 furin-cleavage site or introducing it into the SARS-CoV-1 spike. Pseudovirus entry assays with cathepsin vs. TMPRSS2 pathway inhibitors, spike furin-site mutagenesis, combination drug treatment experiments PLoS pathogens High 33465165
2017 Wild-type clinical isolates of human coronaviruses HCoV-OC43 and HCoV-HKU1 prefer cell-surface TMPRSS2 over endosomal cathepsins for cell entry in human airway epithelial cells; cell-culture-adapted HCoV-OC43 lost the ability to infect air-liquid interface cultures of human bronchial tracheal epithelial cells. Viral infection assays with cell-surface vs. endosomal pathway inhibitors, comparison of clinical isolates vs. cell-culture-adapted strains, air-liquid interface culture infection Virology Medium 29217279
2022 Furin and TMPRSS2 act synergistically in SARS-CoV-2 S protein processing and viral entry: furin primes S at S1/S2, and TMPRSS2-mediated ACE2 shedding is required for TMPRSS2-mediated enhancement of cell-to-cell fusion in the absence of S1/S2 priming; the collectrin dimerization domain of ACE2 is essential for the TMPRSS2 effect on fusion; the S2' cleavage site was identified as KPS815↓ and is strongly enhanced by ACE2 engagement. Proteomics identification of S2' cleavage site, pharmacological furin inhibitors (BOS), camostat (TMPRSS2 inhibitor), quantitative cell-to-cell fusion assays, ACE2 domain deletion experiments, SARS-CoV-2 infection of Calu-3 cells Journal of virology High 35343766
2022 The small-molecule TMPRSS2 inhibitor N-0385 exhibits low nanomolar potency against SARS-CoV-2 in human lung cells and colonoids; in K18-hACE2 transgenic mice, N-0385 provides high-level prophylactic and therapeutic benefit after multiple or single administrations, demonstrating that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo. In vitro potency assays in Calu-3 and colonoids, K18-hACE2 transgenic mouse model, prophylactic and therapeutic dosing regimens, multiple variant testing Nature High 35344983
2020 HAI-2 (hepatocyte growth factor activator inhibitor-2) is a cognate inhibitor of TMPRSS2: HAI-2 binds TMPRSS2 with high affinity, co-localizes with TMPRSS2, inhibits TMPRSS2 proteolytic activity through both KD1 and KD2 domains, suppresses TMPRSS2-induced pro-HGF activation and extracellular matrix degradation, and blocks TMPRSS2-induced prostate cancer metastasis in orthotopic xenograft mice. Co-immunoprecipitation with LC/MS/MS identification, recombinant protein inhibitory assays, immunofluorescence co-localization, pro-HGF activation assay, invasion assay, orthotopic xenograft mouse model Oncogene High 32778768
2020 DNA damage induces proteasomal degradation of TMPRSS2-ERG oncoprotein through ERG Thr-187 and Tyr-190 phosphorylation by GSK3β and WEE1 kinases respectively; dual phosphorylation triggers recognition and ubiquitin-mediated degradation by the E3 ligase FBW7 independent of a canonical degron. PTEN deletion or GSK3β inactivation abolishes this degradation. Phosphorylation site mutagenesis, kinase knockdown/inhibition (GSK3β, WEE1), co-immunoprecipitation with FBW7, proteasome inhibitor experiments, in vitro cell culture and mouse xenograft chemotherapy resistance experiments Molecular cell High 32871104
2019 AR/FOXA1 binding to enhancers E1 and E2 on chromosome 21 mediates chromatin looping that co-regulates both TMPRSS2 and PRCAT38; acetyltransferase p300 activity mediates loop formation and enhancer activity; knockout of either enhancer simultaneously impaired transcription of both genes and inhibited cell growth and migration. ChIP-seq, chromatin conformation capture (looping assays), CRISPR enhancer knockout, qRT-PCR, cell proliferation and migration assays Cells Medium 31405024
2021 IL-1β promotes TMPRSS2 expression and SARS-CoV-2 cell entry through the p38 MAPK–GATA2 signaling axis in lung epithelial cells. Cytokine treatment of cells, p38 MAPK inhibitors, GATA2 manipulation, TMPRSS2 expression measurement, pseudovirus/viral infection assays Frontiers in immunology Medium 34950146
2022 An RNA G-quadruplex (RG4) structure within the TMPRSS2 mRNA inhibits TMPRSS2 translation; G4-stabilizing compounds attenuate SARS-CoV-2 infection in pseudovirus cell systems and mouse models; TMPRSS2 protein is increased in lungs of COVID-19 patients, consistent with loss of RG4-mediated translational repression. Bioinformatics RG4 prediction, biochemical/biophysical RG4 assays, translation reporter assays, G4 stabilizer treatment, pseudovirus infection, mouse infection model, COVID-19 patient lung protein analysis Nature communications Medium 35301316
2023 PM2.5 activates AhR which translocates to the nucleus, binds the TMPRSS2 promoter, and upregulates TMPRSS2 and IL-18 expression to promote lung cancer progression; TMPRSS2 depletion in lung cancer cells suppressed anchorage-independent growth and xenograft tumor growth in mice. AhR nuclear translocation and ChIP at TMPRSS2 promoter, siRNA/shRNA TMPRSS2 knockdown, xenograft mouse model, anchorage-independent growth assay, PM2.5 long-term exposure cell model EMBO molecular medicine Medium 36975376
2022 Antithrombin (AT) binds and inhibits TMPRSS2 as shown by molecular docking and enzyme activity assays; AT blocks entry of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and Omicron spike-driven entry; activation of AT by heparin or fondaparinux increases its anti-TMPRSS2 activity. Molecular docking, TMPRSS2 enzymatic activity assays, spike pseudovirus entry assays, authentic SARS-CoV-2 lung cell infection, anticoagulant activation experiments Journal of medical virology Medium 36056630
2022 Lactoferricin and the N-terminal lactoferrin peptide pLF1 inhibit TMPRSS2 proteolytic activity, block SARS-CoV-2 spike protein processing, and inhibit SARS-CoV-2 infection of permissive cells. TMPRSS2 enzymatic activity assay, spike cleavage assay, SARS-CoV-2 pseudovirus and authentic virus infection assays Frontiers in immunology Medium 36081512
2022 Peptidomimetic compounds designed to target the TMPRSS2 catalytic site inhibit TMPRSS2 serine protease activity, block SARS-CoV-2 spike pseudovirus entry, and inhibit authentic SARS-CoV-2 infection (including Delta and Omicron BA.1) with comparable efficacy to camostat mesylate; inhibitors are stable in blood serum/plasma. Molecular docking, TMPRSS2 enzymatic inhibition assays, SARS-CoV-2 pseudovirus entry assays, authentic SARS-CoV-2 infection assays, serum/plasma stability assays Communications biology Medium 35804152
2001 TMPRSS2 is expressed in the epithelia of gastrointestinal, urogenital, and respiratory tracts in mice; in both mouse and human prostate, expression is localized to luminal epithelial cells. Mouse TMPRSS2 predicted protein shares 81.4% similarity with human TMPRSS2. Mouse TMPRSS2 cDNA cloning, Northern blot, in situ hybridization of mouse embryos and adult tissues, comparative expression analysis The Journal of pathology Medium 11169526
2011 TMPRSS2-ERG fusion product (but not wild-type ERG) negatively regulates PSMA expression at the transcriptional level; androgen stimulation increases TMPRSS2-ERG expression in VCaP cells, leading to decreased PSMA mRNA; ERG siRNA knockdown in VCaP cells enhances PSMA expression; TMPRSS2-ERG overexpression in LNCaP cells downregulates PSMA in a PSMA-luciferase reporter assay. siRNA knockdown of ERG, TMPRSS2-ERG overexpression in LNCaP cells, PSMA luciferase reporter assay, androgen treatment, flutamide (androgen antagonist) treatment PloS one Medium 21731703
2019 TMPRSS2-ERG fusion protein directly and specifically regulates expression of the α1 and β1 subunits of soluble guanylyl cyclase (sGC), activating NO-cGMP-PKG signaling; ERG increases cGMP synthesis and PKG activity in prostate cancer cells; sGC inhibitor treatment represses tumor growth in TMPRSS2-ERG-positive PCa xenograft models and synergizes with enzalutamide. ChIP-seq, gene expression profiling, cGMP assay, PKG activity assay, sGC inhibitor treatment in xenograft models, ERG knockdown Oncogene Medium 30718921
2018 TMPRSS2-ERG fusion product mediates prostate oncogenesis by binding to BAF (mammalian SWI/SNF) ATP-dependent chromatin remodeling complexes; ERG drives genome-wide retargeting of BAF complexes in an ETS DNA-motif-dependent manner; ERG requires intact BAF complexes for chromatin occupancy and BAF ATPase activity for target gene regulation; in prostate organoids, BAF complexes are required for ERG-mediated basal-to-luminal transition. Co-immunoprecipitation, ChIP-seq for ERG and BAF subunits, BAF inhibition/depletion, prostate organoid model, gene expression profiling Molecular cell High 30078722
2017 FOXO1 binds and inhibits the transcriptional activity of prostate cancer-associated ERG (including TMPRSS2-ERG fusion product) independently of FOXO1's own transcriptional activity; knockdown of endogenous FOXO1 increases invasion of TMPRSS2-ERG fusion-positive VCaP cells, an effect abolished by ERG knockdown; combined ERG transgene expression and Foxo1 deletion in mice results in high-grade prostatic intraepithelial neoplasia. Co-immunoprecipitation, ERG luciferase reporter assay, siRNA knockdown (FOXO1, ERG), invasion assay, transgenic/Foxo1-knockout mouse prostate model Cancer research Medium 28986382
2014 TMPRSS2-ERG fusion drives prostate cell proliferation and blocks differentiation to both neuroendocrine (NE) and luminal cell types; ERG represses AR-independent neuronal/NE genes and AR-regulated luminal genes; NE cells generated upon ERG knockdown/AR-inhibition are resistant to pharmacological AR inhibition and can revert to parental phenotype upon AR/ERG signaling restoration. ERG knockdown in TMPRSS2-ERG-positive cell line, ERG transgenic mouse model, transcriptional profiling, cell sorting, proliferation assays, androgen signaling inhibition Oncogene Medium 25263440
2018 BRD4 is essential for repair of DNA double-strand breaks and mediates formation of TMPRSS2-ERG gene rearrangements through the non-homologous end joining (NHEJ) pathway; genome-wide DNA breaks are associated with enhanced H4 acetylation leading to BRD4 recruitment and establishment of the DNA repair complex. BETi pharmacological inhibition, genome-wide DNA break mapping, ChIP for BRD4 and histone acetylation marks, NHEJ functional assays, clinical sample BRD4 protein analysis Cell reports Medium 29346775
2022 TMPRSS2 is identified as a receptor for Paeniclostridium sordellii hemorrhagic toxin (TcsH) via genome-wide CRISPR/Cas9 screens; genetic deletion of TMPRSS2 confers cellular resistance to TcsH intoxication; TMPRSS2 and fucosylated glycans act as independent/redundant receptors both binding TcsH through its CROPs domain; Tmprss2-/- mice are protected from TcsH-induced systemic toxicity and colonic epithelial lesions. Genome-wide CRISPR/Cas9 screen (two parallel screens), TMPRSS2 genetic deletion, binding assays with CROPs domain, Tmprss2-/- mouse model Nature communications High 35882856

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 14365 32142651
2005 Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science (New York, N.Y.) 3138 16254181
2022 Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature 851 35104837
2020 SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. The EMBO journal 821 32246845
2020 TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Science immunology 803 32404436
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2021 TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells. The EMBO journal 285 34159616
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 229 17334343
2017 TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 213 28778717
2020 ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. Frontiers in immunology 212 33117379
2008 Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer research 211 18172298
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 178 33465165
2022 A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature 177 35344983
2017 Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 173 29217279
2022 Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation. Nature chemical biology 164 35676539
2022 Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity. Journal of virology 144 35343766
2001 Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. The Journal of pathology 135 11169526
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2018 BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell reports 125 29346775
2020 Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS computational biology 117 33290397
2021 Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection. Nature communications 113 33741941
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 102 33180746
2020 Targeting TMPRSS2 in SARS-CoV-2 Infection. Mayo Clinic proceedings 100 32861340
2014 TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. PloS one 100 24505269
2023 TMPRSS2 is a functional receptor for human coronavirus HKU1. Nature 90 37879362
2018 Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Molecular cell 89 30078722
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2022 Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways. Nature communications 84 36243815
2021 Contributions of human ACE2 and TMPRSS2 in determining host-pathogen interaction of COVID-19. Journal of genetics 84 33707363
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2021 Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes. Scientific reports 80 34045511
2020 Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2. Journal of medical virology 80 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 68 35301316
2023 PM2.5 promotes lung cancer progression through activation of the AhR-TMPRSS2-IL18 pathway. EMBO molecular medicine 65 36975376
2020 COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie 63 32620366
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 Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions. AIMS microbiology 60 33029570
2022 The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment. International journal of molecular sciences 59 35163273
2020 Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents. Biochemical and biophysical research communications 58 32703421
2017 Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion. Cancer research 55 28986382
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2021 High expression of ACE2 and TMPRSS2 and clinical characteristics of COVID-19 in colorectal cancer patients. NPJ precision oncology 52 33479506
2014 TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene 52 25263440
2020 Expression of ACE2, TMPRSS2, and Furin in Mouse Ear Tissue, and the Implications for SARS-CoV-2 Infection. The Laryngoscope 49 33296096
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2020 ACE2 & TMPRSS2 Expressions in Head & Neck Tissues: A Systematic Review. Head and neck pathology 48 32816230
2022 A common TMPRSS2 variant has a protective effect against severe COVID-19. Current research in translational medicine 43 35104687
2021 Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress. Scientific reports 43 33958627
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 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
2020 DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3β and WEE1. Molecular cell 39 32871104
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2020 Expression of ACE2 and TMPRSS2 Proteins in the Upper and Lower Aerodigestive Tracts of Rats: Implications on COVID 19 Infections. The Laryngoscope 35 32940922
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2021 ACE2 and TMPRSS2 in human saliva can adsorb to the oral mucosal epithelium. Journal of anatomy 31 34590312
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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 Computational analysis of TMPRSS2 expression in normal and SARS-CoV-2-infected human tissues. Chemico-biological interactions 26 34284028
2020 GB-2 inhibits ACE2 and TMPRSS2 expression: In vivo and in vitro studies. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 33049583
2023 TMPRSS2 polymorphism (rs12329760) and the severity of the COVID-19 in Iranian population. PloS one 25 36795725
2021 Spiking dependence of SARS-CoV-2 pathogenicity on TMPRSS2. Journal of medical virology 25 33638460
2024 Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus. Cell 24 38964326
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 IL1β Promotes TMPRSS2 Expression and SARS-CoV-2 Cell Entry Through the p38 MAPK-GATA2 Axis. Frontiers in immunology 24 34950146
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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
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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
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 18 35804152
2022 Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer. Cell & bioscience 17 36088396
2023 PCA3 and TMPRSS2: ERG Urine Level as Diagnostic Biomarker of Prostate Cancer. Research and reports in urology 16 37181497
2022 Paeniclostridium sordellii hemorrhagic toxin targets TMPRSS2 to induce colonic epithelial lesions. Nature communications 15 35882856
2021 Interactions of renin-angiotensin system and COVID-19: the importance of daily rhythms in ACE2, ADAM17 and TMPRSS2 expression. Physiological research 15 34913351
2016 TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 27320318
2023 Relevance of TMPRSS2, CD163/CD206, and CD33 in clinical severity stratification of COVID-19. Frontiers in immunology 14 36969980
2022 Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by lactoferricin. Frontiers in immunology 14 36081512
2021 Gastrointestinal cancers, ACE-2/TMPRSS2 expression and susceptibility to COVID-19. Cancer cell international 14 34399734
2017 Micro-RNA-204 Participates in TMPRSS2/ERG Regulation and Androgen Receptor Reprogramming in Prostate Cancer. Hormones & cancer 14 28050800
2020 Covid-19 pathogenesis in prostatic cancer and TMPRSS2-ERG regulatory genetic pathway. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 13 33301988

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