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TMPRSS2
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<h2 id="function">Function</h2> <p>The <i>TMPRSS2</i> gene encodes a protein that belongs to the <a href="/facts/Serine_protease/kGfEE6hE">serine protease</a> family. The encoded protein contains a type II transmembrane <a href="/facts/Domain_(protein)/oUpFcSsl">domain</a>, a <a href="/facts/Low-density_lipoprotein_receptor_gene_family/eRGYxfgx">low density lipoprotein receptor class A domain</a>, a <a href="/facts/Scavenger_receptor_cysteine-rich_domain/6YMsqVCv">scavenger receptor cysteine-rich domain</a> and a protease domain. Serine proteases are known to be involved in many physiological and <a href="/facts/Pathology/U9b18LJG">pathological processes</a>. This gene is up-regulated by <a href="/facts/Androgenic_hormone/Rxey0HxX">androgenic hormones</a> in <a href="/facts/Prostate_cancer/Mx7XuDhm">prostate cancer</a> cells and down-regulated in <a href="/facts/Hormone-refractory_prostate_cancer/Mx7XuDhm">androgen-independent prostate cancer</a> tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after <a href="/facts/Proteolysis/GtQdv6J7">autocleavage</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> <i>TMPRSS2</i> participates in proteolytic cascades necessary for normal physiological function of the prostate.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> Gene <a href="/facts/Knockout_mice/Aw50cobf">knockout mice</a> lacking <i>TMPRSS2</i> show no abnormalities.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="structure">Structure</h2> <p>As a type II transmembrane <a href="/facts/Protease/G1ASdVat">protease</a>, TMPRSS2 consists of an intracellular <a href="/facts/N-terminus/yKYpuaBJ">N-terminal domain</a>, a <a href="/facts/Transmembrane_domain/D1j0PwSR">transmembrane domain</a>, a stem region that extends extracellularly and a <a href="/facts/C-terminal/ws4scHgT">C-terminal</a> domain that catalyzes its <a href="/facts/Serine_protease/kGfEE6hE">serine protease</a> (SP) activity.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> This serine protease activity is orchestrated by a <a href="/facts/Catalytic_triad/WskaH1zM">catalytic triad</a> containing the residues His296, Asp345, and Ser441.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues (<a href="/facts/Lysine/CEetgA9L">lysine</a> or <a href="/facts/Arginine/y49Hdf1e">arginine</a> residues)— consistent with what is observed in the S1/S2 cleavage site found in <a href="/facts/SARS-CoV-2/DxF8rDc1">SARS-CoV-2</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside another <a href="/facts/Structural_motif/g8EBDBGW">motif</a> in the stem region: the scavenger receptor cysteine-rich domain (SRCR).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> This domain may be implicated in the binding of <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular molecules</a> and other nearby cells.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overall <a href="/facts/Virulence/TYmX1Fa6">virulence</a> of SARS-CoV-2.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <h3>In prostate cancer</h3> <p class="note">See also: <a href="/facts/ERG_(gene)/Y0p4Elgj">ERG (gene) § TMPRSS2 gene fusion</a></p> <p>TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of <a href="/facts/ETS_transcription_factors/wkE1y5hk">ETS transcription factors</a>, such as <i><a href="/facts/ERG_(gene)/Y0p4Elgj">ERG</a></i> and <i><a href="/facts/ETV1/mCGkDuLs">ETV1</a></i>, through <a href="/facts/Gene_fusion/AyR9DgQ8">gene fusion</a>. 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 <a href="/facts/Androgen_receptor/NBPRszqm">androgen receptor</a> signaling.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h3>Coronaviruses</h3> <p>Some coronaviruses, e.g. <a href="/facts/Severe_acute_respiratory_syndrome_coronavirus/jXYCe6w5">SARS-CoV-1</a>, <a href="/facts/Middle_East_respiratory_syndrome_coronavirus/a5LDpoW8">MERS-CoV</a>, and <a href="/facts/Severe_acute_respiratory_syndrome_coronavirus_2/DxF8rDc1">SARS-CoV-2</a> (although less well by the <a href="/facts/Omicron_variant/N6u1sGPt">omicron variant</a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a>), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> <a href="/facts/SARS-CoV-2/DxF8rDc1">SARS-CoV-2</a> uses the SARS-CoV receptor <a href="/facts/ACE2/jCDTv3ur">ACE2</a> for entry and the serine protease TMPRSS2 for S protein priming.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p><p>Cleavage of the <a href="/facts/SARS-CoV-2/DxF8rDc1">SARS-CoV-2</a> <a href="/facts/Coronavirus_spike_protein/JTcbvUn2">S2</a> <a href="/facts/Coronavirus_spike_protein/JTcbvUn2">spike protein</a> required for viral entry into cells can be accomplished by <a href="/facts/Protease/G1ASdVat">proteases</a> TMPRSS2 located on the cell membrane, or by <a href="/facts/Cathepsin/c8vK49zn">cathepsins</a> (primarily <a href="/facts/Cathepsin_L1/RIftLTSH">cathepsin L</a>) in <a href="/facts/Endosome/CYsyuJ75">endolysosomes</a>.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> <a href="/facts/Hydroxychloroquine/cQkRhGIs">Hydroxychloroquine</a> 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.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p><p>The enzyme <a href="/facts/Adam17/QCQUw2uY">Adam17</a> has similar <a href="/facts/Angiotensin-converting_enzyme_2/jCDTv3ur">ACE2</a> cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p><p>A TMPRSS2 inhibitor such as <a href="/facts/Camostat/Gw2Gk244">camostat</a> approved for clinical use blocked entry and might constitute a treatment option.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> 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 <a href="/facts/COVID-19/YsUgvsaX">COVID-19</a>, is the over-the-counter (in most countries) mucolytic cough medicine <a href="/facts/Bromhexine/ccXQVacM">bromhexine</a>,<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> which is also being investigated as a possible treatment for COVID-19 itself as well.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p><p>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 <a href="/facts/Prostate/mrBdSsf7">prostate</a> <a href="/facts/Epithelium/ecKHcHC3">epithelium</a> than any tissue, suggests a role for TMPRSS2 in the gender difference.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> <a href="/facts/Prostate_cancer/Mx7XuDhm">Prostate cancer</a> patients receiving <a href="/facts/Androgen_deprivation_therapy/KCJxJ8xL">androgen deprivation therapy</a> have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> </p> <h2 id="inhibitors">Inhibitors</h2> <p><a href="/facts/Camostat/Gw2Gk244">Camostat</a> is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat <a href="/facts/Pancreatitis/gmbNTcCG">pancreatitis</a> and <a href="/facts/Reflux_esophagitis/pgLYnRt1">reflux esophagitis</a>.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> It was found not to be effective against COVID-19.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". <i>Gene</i>. 138 (1–2): 171–174. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0378-1119%2894%2990802-8">10.1016/0378-1119(94)90802-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8125298">8125298</a>.</li> <li>Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". <i>Gene</i>. 200 (1–2): 149–156. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0378-1119%2897%2900411-3">10.1016/S0378-1119(97)00411-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9373149">9373149</a>.</li> <li>Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, et al. (September 1999). <a href="http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10485450">"Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2"</a>. <i>Cancer Research</i>. 59 (17): 4180–4184. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10485450">10485450</a>.</li> <li>Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT (January 2001). "Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues". <i>The Journal of Pathology</i>. 193 (1): 134–140. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2F1096-9896%282000%299999%3A9999%3C%3A%3AAID-PATH743%3E3.0.CO%3B2-T">10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11169526">11169526</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:37552020">37552020</a>.</li> <li>Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, et al. (February 2001). <a href="http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11245484">"Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia"</a>. <i>Cancer Research</i>. 61 (4): 1686–1692. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11245484">11245484</a>.</li> <li>Jacquinet E, Rao NV, Rao GV, Zhengming W, Albertine KH, Hoidal JR (May 2001). <a href="https://doi.org/10.1046%2Fj.1432-1327.2001.02165.x">"Cloning and characterization of the cDNA and gene for human epitheliasin"</a>. <i>European Journal of Biochemistry</i>. 268 (9): 2687–2699. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1046%2Fj.1432-1327.2001.02165.x">10.1046/j.1432-1327.2001.02165.x</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11322890">11322890</a>.</li> <li>Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK (June 2001). "Mutation analyses of 268 candidate genes in human tumor cell lines". <i>Genomics</i>. 74 (3): 352–364. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fgeno.2001.6551">10.1006/geno.2001.6551</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11414763">11414763</a>.</li> <li>Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S (June 2005). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183478">"The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells"</a>. <i>The Biochemical Journal</i>. 388 (Pt 3): 967–972. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1042%2FBJ20041066">10.1042/BJ20041066</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183478">1183478</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15537383">15537383</a>.</li> <li>Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I (July 2006). "Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer". <i>Genes, Chromosomes & Cancer</i>. 45 (7): 717–719. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fgcc.20329">10.1002/gcc.20329</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16575875">16575875</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:86518137">86518137</a>.</li> <li>Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, et al. (April 2006). <a href="https://doi.org/10.1158%2F0008-5472.CAN-06-0168">"TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer"</a>. <i>Cancer Research</i>. 66 (7): 3396–3400. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1158%2F0008-5472.CAN-06-0168">10.1158/0008-5472.CAN-06-0168</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16585160">16585160</a>.</li> <li>Yoshimoto M, Joshua AM, Chilton-Macneill S, Bayani J, Selvarajah S, Evans AJ, et al. (June 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1601467">"Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement"</a>. <i>Neoplasia</i>. 8 (6): 465–469. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1593%2Fneo.06283">10.1593/neo.06283</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1601467">1601467</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16820092">16820092</a>.</li> <li>Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M (October 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617224">"Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium"</a>. <i>Journal of Virology</i>. 80 (19): 9896–9898. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2FJVI.01118-06">10.1128/JVI.01118-06</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617224">1617224</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16973594">16973594</a>.</li> <li>Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jerónimo C, Teixeira MR (October 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1715930">"TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions"</a>. <i>Neoplasia</i>. 8 (10): 826–832. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1593%2Fneo.06427">10.1593/neo.06427</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1715930">1715930</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17032499">17032499</a>.</li> <li>Yoo NJ, Lee JW, Lee SH (March 2007). "Absence of fusion of TMPRSS2 and ETS transcription factor genes in gastric and colorectal carcinomas". <i>APMIS</i>. 115 (3): 252–253. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1111%2Fj.1600-0463.2007.apm_652.x">10.1111/j.1600-0463.2007.apm_652.x</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17367471">17367471</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:34487156">34487156</a>.</li> <li>Winnes M, Lissbrant E, Damber JE, Stenman G (May 2007). <a href="https://doi.org/10.3892%2For.17.5.1033">"Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer"</a>. <i>Oncology Reports</i>. 17 (5): 1033–1036. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.3892%2For.17.5.1033">10.3892/or.17.5.1033</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17390040">17390040</a>.</li> <li>Tu JJ, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen YT (September 2007). <a href="https://doi.org/10.1038%2Fmodpathol.3800903">"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"</a>. <i>Modern Pathology</i>. 20 (9): 921–928. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fmodpathol.3800903">10.1038/modpathol.3800903</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17632455">17632455</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). 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