View source for TMPRSS2

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{{Short description|Protein-coding gene in humans}}
{{Infobox_gene}}
'''Transmembrane protease, serine 2''' is an [[enzyme]] that in humans is encoded by the '''''TMPRSS2''''' [[gene]].<ref name="pmid9325052">{{cite journal | vauthors = Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE | title = Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3 | journal = Genomics | volume = 44 | issue = 3 | pages = 309–320 | date = September 1997 | pmid = 9325052 | doi = 10.1006/geno.1997.4845 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TMPRSS2 transmembrane protease, serine 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7113}}</ref><ref name="uniprot">{{cite web | title = UniProt Protein: TMPS2_HUMAN transmembrane protease | url = https://www.uniprot.org/uniprot/O15393#function}}</ref> It belongs to the [[TMPRSS]] family of proteins, whose members are [[transmembrane protein]]s which have a [[serine protease]] activity.<ref name="Thunders-2020">{{cite journal | vauthors = Thunders M, Delahunt B | title = Gene of the month: ''TMPRSS2'' (transmembrane serine protease 2) | journal = Journal of Clinical Pathology | volume = 73 | issue = 12 | pages = 773–776 | date = December 2020 | pmid = 32873700 | pmc = 7470178 | doi = 10.1136/jclinpath-2020-206987 }}</ref> The TMPRSS2 protein is found in high concentration in the [[cell membrane]]s of [[epithelial cells]] of the [[lung]] and of the [[prostate]], but also in the [[heart]], [[liver]] and [[gastrointestinal tract]].<ref name="Thunders-2020" />

Mutations of the ''TMPRSS2'' gene are often involved in [[prostate cancer]]. Several viruses, including [[Severe acute respiratory syndrome coronavirus 2|SARS-CoV-2]], use the protease activity of the TMPRSS2 protein in the process of entering cells.<ref name="Thunders-2020" />

== Function ==
The ''TMPRSS2'' gene encodes a protein that belongs to the [[serine protease]] family. The encoded protein contains a type II transmembrane [[domain (protein)|domain]], a [[Low-density lipoprotein receptor gene family#Class A|low density lipoprotein receptor class A domain]], a [[scavenger receptor cysteine-rich domain]] and a protease domain. Serine proteases are known to be involved in many physiological and [[Pathology|pathological processes]]. This gene is up-regulated by [[androgenic hormone]]s in [[prostate cancer]] cells and down-regulated in [[hormone-refractory prostate cancer|androgen-independent prostate cancer]] tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after [[Proteolysis#Autoproteolysis|autocleavage]].<ref name="entrez" /> ''TMPRSS2'' participates in proteolytic cascades necessary for normal physiological function of the prostate.<ref name="uniprot" /> Gene [[knockout mice]] lacking ''TMPRSS2'' show no abnormalities.<ref name="pmid34336361">{{cite journal | vauthors = Sarker J, Das P, Sarker S, Roy AK, Momen AZ | title = A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation | journal = Scientifica | volume = 2021 | pages = 2706789 | date = 2021 | pmid = 34336361 | pmc = 8313365 | doi = 10.1155/2021/2706789 | doi-access = free }}</ref>

== Structure ==
[[File:His296,_Asp345,_and_Ser441_catalytic_triad.png|thumb|His296, Asp345, and Ser441 catalytic triad within the Serine Peptidase domain on TMPRSS2 that is characteristic of almost all Type II Serine proteases. The serine (green) engages in [[Nucleophile|nucleophilic attack]], the histidine (cyan) acts as a general [[Base (chemistry)|base]] to reset the [[serine]] and the [[Aspartic acid|aspartate]] (magenta) neutralizes the [[histidine]] in [[Transition state|transition states]] during reactions that cause proteolytic cleavage. This structure was solved via [[X-ray crystallography]] with a resolution of 1.95 [[Angstrom|Angstroms]] (PDB: 7MEQ).<ref name="Fraser-2022">{{cite journal | vauthors = Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith CH, Bénard F | display-authors = 6 | title = Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation | journal = Nature Chemical Biology | volume = 18 | issue = 9 | pages = 963–971 | date = September 2022 | pmid = 35676539 | doi = 10.1038/s41589-022-01059-7 | doi-access = free }}</ref> Image made in [[UCSF Chimera|Chimera]].<ref>{{Cite web |title=Supplemental Information 4: UCSF Chimera |doi=10.7717/peerj.4593/supp-4 |doi-access=free }}</ref>]]
[[File:TMPRSS2-_Solved_Structure.png|thumb|Solved structure of TMPRSS2 is shown here (PDB: 7MEQ)[https://www.uniprot.org/uniprotkb/O15393/entry], the entire protein is oriented with the [[extracellular]] side towards the top and the [[Cytoplasm|cytoplasmic]] side towards the bottom.<ref name="Fraser-2022" /> Bound [[Calcium in biology|calcium ions]] are shown in blue and function as stabilizing [[Cofactor (biochemistry)|cofactors]]. This view (generated in Chimera) illustrates the largely [[Protein conformation|open conformation]] that exposes the [[catalytic triad]].]]
As a type II transmembrane [[protease]], TMPRSS2 consists of an intracellular [[N-terminus|N-terminal domain]], a [[transmembrane domain]], a stem region that extends extracellularly and a [[C-terminal]] domain that catalyzes its [[serine protease]] (SP) activity.<ref name="Wettstein-2022">{{cite journal | vauthors = Wettstein L, Kirchhoff F, Münch J | title = The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | pages = 1351 | date = January 2022 | pmid = 35163273 | pmc = 8836196 | doi = 10.3390/ijms23031351 | doi-access = free }}</ref> This serine protease activity is orchestrated by a [[catalytic triad]] containing the residues His296, Asp345, and Ser441.<ref name="Wettstein-2022" /><ref name="Fraser-2022" /> This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues ([[lysine]] or [[arginine]] residues)— consistent with what is observed in the S1/S2 cleavage site found in [[SARS-CoV-2]].<ref name="Wettstein-2022" /> A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).<ref name="Wettstein-2022" /> Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside another [[Structural motif|motif]] in the stem region: the scavenger receptor cysteine-rich domain (SRCR).<ref name="Wettstein-2022" /> This domain may be implicated in the binding of [[Extracellular matrix|extracellular molecules]] and other nearby cells.<ref>{{cite journal | vauthors = Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE | title = Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3 | journal = Genomics | volume = 44 | issue = 3 | pages = 309–320 | date = September 1997 | pmid = 9325052 | doi = 10.1006/geno.1997.4845 }}</ref><ref>{{cite journal | vauthors = Wettstein L, Kirchhoff F, Münch J | title = The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | pages = 1351 | date = January 2022 | pmid = 35163273 | pmc = 8836196 | doi = 10.3390/ijms23031351 | doi-access = free }}</ref> Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overall [[virulence]] of SARS-CoV-2.<ref>{{cite journal | vauthors = Guipponi M, Antonarakis SE, Scott HS | title = TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness | journal = Frontiers in Bioscience | volume = 13 | issue = 13 | pages = 1557–1567 | date = January 2008 | pmid = 17981648 | doi = 10.2741/2780 | doi-access = free }}</ref><ref name="Wettstein-2022" /><ref>{{cite journal | vauthors = Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, Raitano AB, Jakobovits A | display-authors = 6 | title = Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia | journal = Cancer Research | volume = 61 | issue = 4 | pages = 1686–1692 | date = February 2001 | pmid = 11245484 | url = https://pubmed.ncbi.nlm.nih.gov/11245484 }}</ref>

== Clinical significance ==

=== In prostate cancer ===
{{See also|ERG (gene)#TMPRSS2 gene fusion}}
TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of [[ETS transcription factors]], such as ''[[ERG (gene)|ERG]]'' and ''[[ETV1]]'', through [[gene fusion]]. TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of [[androgen receptor]] signaling.<ref>{{cite journal | vauthors = Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM | display-authors = 6 | title = An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression | journal = Cancer Cell | volume = 17 | issue = 5 | pages = 443–454 | date = May 2010 | pmid = 20478527 | pmc = 2874722 | doi = 10.1016/j.ccr.2010.03.018 }}</ref>

=== Coronaviruses ===
Some coronaviruses, e.g. [[Severe acute respiratory syndrome coronavirus|SARS-CoV-1]], [[Middle East respiratory syndrome coronavirus|MERS-CoV]], and [[Severe acute respiratory syndrome coronavirus 2|SARS-CoV-2]] (although less well by the [[omicron variant]]<ref name="pmid35104837">{{cite journal | vauthors = Meng B, Abdullahi A, Ferreira IA, Goonawardane N, Saito A, Kimura I, Yamasoba D, Gerber PP, Fatihi S, Rathore S, Zepeda SK, Papa G, Kemp SA, Ikeda T, Toyoda M, Tan TS, Kuramochi J, Mitsunaga S, Ueno T, Shirakawa K, Takaori-Kondo A, Brevini T, Mallery DL, Charles OJ, Bowen JE, Joshi A, Walls AC, Jackson L, Martin D, Smith KG, Bradley J, Briggs JA, Choi J, Madissoon E, Meyer KB, Mlcochova P, Ceron-Gutierrez L, Doffinger R, Teichmann SA, Fisher AJ, Pizzuto MS, de Marco A, Corti D, Hosmillo M, Lee JH, James LC, Thukral L, Veesler D, Sigal A, Sampaziotis F, Goodfellow IG, Matheson NJ, Sato K, Gupta RK | display-authors = 6 | title = Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity | journal = Nature | volume = 603 | issue = 7902 | pages = 706–714 | date = March 2022 | pmid = 35104837 | pmc = 8942856 | doi = 10.1038/s41586-022-04474-x | bibcode = 2022Natur.603..706M }}</ref>), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.<ref>{{cite journal | vauthors = Huggins DJ | title = Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2 | journal = Journal of Molecular Graphics & Modelling | volume = 100 | pages = 107710 | date = November 2020 | pmid = 32829149 | pmc = 7417922 | doi = 10.1016/j.jmgm.2020.107710 }}</ref><ref name="Hoffmann_2020" /> [[SARS-CoV-2]] uses the SARS-CoV receptor [[ACE2]] for entry and the serine protease TMPRSS2 for S protein priming.<ref>{{cite journal | vauthors = Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H | title = Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2) | journal = Molecules | volume = 25 | issue = 10 | pages = 2271 | date = May 2020 | pmid = 32408547 | pmc = 7287752 | doi = 10.3390/molecules25102271 | doi-access = free }}</ref>

Cleavage of the [[SARS-CoV-2]] [[Coronavirus spike protein#S2|S2]] [[Coronavirus spike protein|spike protein]] required for viral entry into cells can be accomplished by [[protease]]s TMPRSS2 located on the cell membrane, or by [[cathepsin]]s (primarily [[Cathepsin L1|cathepsin L]]) in [[Endosome#Late endosomes to lysosomes|endolysosomes]].<ref name="pmid34611326">{{cite journal | vauthors = Jackson CB, Farzan M, Chen B, Choe H | title = Mechanisms of SARS-CoV-2 entry into cells | journal = Nature Reviews. Molecular Cell Biology | volume = 23 | issue = 1 | pages = 3–20 | date = January 2022 | pmid = 34611326 | pmc = 8491763 | doi = 10.1038/s41580-021-00418-x }}</ref> [[Hydroxychloroquine]] inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.<ref name="pmid34611326" />

The enzyme [[Adam17]] has similar [[Angiotensin-converting enzyme 2|ACE2]] cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.<ref name="pmid33117379">{{cite journal | vauthors = Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER | title = ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19 | journal = Frontiers in Immunology | volume = 11 | pages = 576745 | date = 2020 | pmid = 33117379 | pmc = 7575774 | doi = 10.3389/fimmu.2020.576745 | doi-access = free }}</ref> By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.<ref name="pmid33117379" />

A TMPRSS2 inhibitor such as [[camostat]] approved for clinical use blocked entry and might constitute a treatment option.<ref name="Hoffmann_2020">{{cite journal | vauthors = Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S | display-authors = 6 | title = SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor | journal = Cell | volume = 181 | issue = 2 | pages = 271–280.e8 | date = April 2020 | pmid = 32142651 | pmc = 7102627 | doi = 10.1016/j.cell.2020.02.052 | doi-access = free }}
*{{lay source |template = cite press release|url = https://www.dpz.eu/en/home/single-view/news/die-vermehrung-von-sars-coronavirus-2-im-menschen-verhindern.html|title = Preventing spread of SARS coronavirus-2 in humans|date= March 5, 2020 |website = German Primate Center}}</ref><ref name="pmid34611326"/>  Another experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent of [[COVID-19]], is the over-the-counter (in most countries) mucolytic cough medicine [[bromhexine]],<ref name=Shen_2017>{{cite journal | vauthors = Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W | title = TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections | journal = Biochimie | volume = 142 | pages = 1–10 | date = November 2017 | pmid = 28778717 | pmc = 7116903 | doi = 10.1016/j.biochi.2017.07.016 }}</ref> which is also being investigated as a possible treatment for COVID-19 itself as well.<ref name=Depfenhart_2020>{{cite journal | vauthors = Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S | title = Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? | journal = Internal and Emergency Medicine | volume = 15 | issue = 5 | pages = 801–812 | date = August 2020 | pmid = 32458206 | pmc = 7249615 | doi = 10.1007/s11739-020-02383-3 }}</ref> The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.<ref name="pmid34336361" />

The fact that severe illness and death from Sars-Cov-2 is more common in males than females, and that TMPRSS2 is expressed several times more highly in [[prostate]] [[epithelium]] than any tissue, suggests a role for TMPRSS2 in the gender difference.<ref name="pmid32658591">{{cite journal | vauthors = Mollica V, Rizzo A, Massari F | title = The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer | journal = Future Oncology | volume = 16 | issue = 27 | pages = 2029–2033 | date = September 2020 | pmid = 32658591 | pmc = 7359420 | doi = 10.2217/fon-2020-0571 }}</ref><ref name="pmid34420994">{{cite journal | vauthors = Epstein RJ | title = The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor | journal = Tumour Biology | volume = 43 | issue = 1 | pages = 159–176 | date = 2021 | pmid = 34420994 | doi = 10.3233/TUB-211502 | s2cid = 237268413 | doi-access = free }}</ref> [[Prostate cancer]] patients receiving [[androgen deprivation therapy]] have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.<ref name="pmid32658591" /><ref name="pmid34420994" />

== Inhibitors ==
[[Camostat]] is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat [[pancreatitis]] and [[reflux esophagitis]].<ref name="pmid33176395">{{cite journal |vauthors=Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, Cases-Thomas M, Little P, Nielsen LP, Søgaard OS, Kjolby M |title=Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety |journal=Basic & Clinical Pharmacology & Toxicology |volume=128 |issue=2 |pages=204–212 |date=February 2021 |pmid=33176395 |doi=10.1111/bcpt.13533|doi-access=free }}</ref> It was found not to be effective against COVID-19.<ref>{{Cite web|title=ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19|url=https://www.eurekalert.org/pub_releases/2021-06/actg-aac062421.php|access-date=2021-07-01|website=EurekAlert!|language=en}}</ref> A novel inhibitor of TMPRSS2 ([[N-0385]]) has been found to be effective against SARS-CoV-2 infection in cell and animal models.<ref>{{cite journal | vauthors = Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, Jager M, Désilets A, Gao G, Martins M, Vandal T, Thompson CA, Chin A, Rees WD, Steiner T, Nabi IR, Marsault E, Sahler J, Diel DG, Van de Walle GR, August A, Whittaker GR, Boudreault PL, Leduc R, Aguilar HC, Jean F | display-authors = 6 | title = A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic | journal = Nature | pages = 340–348 | date = March 2022 | volume = 605 | issue = 7909 | pmid = 35344983 | doi = 10.1038/s41586-022-04661-w | pmc = 9095466 | bibcode = 2022Natur.605..340S }}</ref><ref name="pmid38548023">{{cite journal |vauthors=Pérez-Vargas J, Lemieux G, Thompson CA, Désilets A, Ennis S, Gao G, Gordon DG, Schulz AL, Niikura M, Nabi IR, Krajden M, Boudreault PL, Leduc R, Jean F |title=Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals |journal=Antiviral Research |volume=225 |issue= |pages=105869 |date=May 2024 |pmid=38548023 |doi=10.1016/j.antiviral.2024.105869|doi-access=free }}</ref>

== References ==
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== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–174 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–156 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, Hood L, Nelson PS | display-authors = 6 | title = Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2 | journal = Cancer Research | volume = 59 | issue = 17 | pages = 4180–4184 | date = September 1999 | pmid = 10485450 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10485450 }}
* {{cite journal | vauthors = Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT | title = Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues | journal = The Journal of Pathology | volume = 193 | issue = 1 | pages = 134–140 | date = January 2001 | pmid = 11169526 | doi = 10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T | s2cid = 37552020 }}
* {{cite journal | vauthors = Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, Raitano AB, Jakobovits A | display-authors = 6 | title = Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia | journal = Cancer Research | volume = 61 | issue = 4 | pages = 1686–1692 | date = February 2001 | pmid = 11245484 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11245484 }}
* {{cite journal | vauthors = Jacquinet E, Rao NV, Rao GV, Zhengming W, Albertine KH, Hoidal JR | title = Cloning and characterization of the cDNA and gene for human epitheliasin | journal = European Journal of Biochemistry | volume = 268 | issue = 9 | pages = 2687–2699 | date = May 2001 | pmid = 11322890 | doi = 10.1046/j.1432-1327.2001.02165.x | doi-access = free }}
* {{cite journal | vauthors = Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK | title = Mutation analyses of 268 candidate genes in human tumor cell lines | journal = Genomics | volume = 74 | issue = 3 | pages = 352–364 | date = June 2001 | pmid = 11414763 | doi = 10.1006/geno.2001.6551 }}
* {{cite journal | vauthors = Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S | title = The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells | journal = The Biochemical Journal | volume = 388 | issue = Pt 3 | pages = 967–972 | date = June 2005 | pmid = 15537383 | pmc = 1183478 | doi = 10.1042/BJ20041066 }}
* {{cite journal | vauthors = Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I | title = Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer | journal = Genes, Chromosomes & Cancer | volume = 45 | issue = 7 | pages = 717–719 | date = July 2006 | pmid = 16575875 | doi = 10.1002/gcc.20329 | s2cid = 86518137 }}
* {{cite journal | vauthors = Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, Cao X, Wei JT, Rubin MA, Shah RB, Chinnaiyan AM | display-authors = 6 | title = TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer | journal = Cancer Research | volume = 66 | issue = 7 | pages = 3396–3400 | date = April 2006 | pmid = 16585160 | doi = 10.1158/0008-5472.CAN-06-0168 | doi-access = free }}
* {{cite journal | vauthors = Yoshimoto M, Joshua AM, Chilton-Macneill S, Bayani J, Selvarajah S, Evans AJ, Zielenska M, Squire JA | display-authors = 6 | title = Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement | journal = Neoplasia | volume = 8 | issue = 6 | pages = 465–469 | date = June 2006 | pmid = 16820092 | pmc = 1601467 | doi = 10.1593/neo.06283 }}
* {{cite journal | vauthors = Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M | title = Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium | journal = Journal of Virology | volume = 80 | issue = 19 | pages = 9896–9898 | date = October 2006 | pmid = 16973594 | pmc = 1617224 | doi = 10.1128/JVI.01118-06 }}
* {{cite journal | vauthors = Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jerónimo C, Teixeira MR | title = TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions | journal = Neoplasia | volume = 8 | issue = 10 | pages = 826–832 | date = October 2006 | pmid = 17032499 | pmc = 1715930 | doi = 10.1593/neo.06427 }}
* {{cite journal | vauthors = Yoo NJ, Lee JW, Lee SH | title = Absence of fusion of TMPRSS2 and ETS transcription factor genes in gastric and colorectal carcinomas | journal = APMIS | volume = 115 | issue = 3 | pages = 252–253 | date = March 2007 | pmid = 17367471 | doi = 10.1111/j.1600-0463.2007.apm_652.x | s2cid = 34487156 }}
* {{cite journal | vauthors = Winnes M, Lissbrant E, Damber JE, Stenman G | title = Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer | journal = Oncology Reports | volume = 17 | issue = 5 | pages = 1033–1036 | date = May 2007 | pmid = 17390040 | doi = 10.3892/or.17.5.1033 | doi-access = free }}
* {{cite journal | vauthors = Tu JJ, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen YT | title = Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues | journal = Modern Pathology | volume = 20 | issue = 9 | pages = 921–928 | date = September 2007 | pmid = 17632455 | doi = 10.1038/modpathol.3800903 | doi-access = free }}
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