ID   TMPS2_HUMAN             Reviewed;         492 AA.
AC   O15393; A8K6Z8; B2R8E5; B7Z459; D3DSJ2; F8WES1; Q6GTK7; Q9BXX1;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   03-OCT-2006, sequence version 3.
DT   17-JUN-2020, entry version 189.
DE   RecName: Full=Transmembrane protease serine 2;
DE            EC=3.4.21.-;
DE   AltName: Full=Serine protease 10;
DE   Contains:
DE     RecName: Full=Transmembrane protease serine 2 non-catalytic chain;
DE   Contains:
DE     RecName: Full=Transmembrane protease serine 2 catalytic chain;
DE   Flags: Precursor;
GN   Name=TMPRSS2; Synonyms=PRSS10;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS MET-160 AND GLN-329.
RX   PubMed=9325052; DOI=10.1006/geno.1997.4845;
RA   Paoloni-Giacobino A., Chen H., Peitsch M.C., Rossier C., Antonarakis S.E.;
RT   "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with
RT   transmembrane, LDLRA, and SRCR domains and maps to 21q22.3.";
RL   Genomics 44:309-320(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT MET-160.
RX   PubMed=11414763; DOI=10.1006/geno.2001.6551;
RA   Teng D.-H., Chen Y., Lian L., Ha P.C., Tavtigian S.V., Wong A.K.C.;
RT   "Mutation analyses of 268 candidate genes in human tumor cell lines.";
RL   Genomics 74:352-364(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF SER-441, FUNCTION,
RP   AND SUBCELLULAR LOCATION.
RX   PubMed=11245484;
RA   Afar D.E.H., Vivanco I., Hubert R.S., Kuo J., Chen E., Saffran D.C.,
RA   Raitano A.B., Jakobovits A.;
RT   "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in
RT   its secretion by prostate and prostate cancer epithelia.";
RL   Cancer Res. 61:1686-1692(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Prostate, Testis, and Tongue;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Liver;
RA   Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA   Tanaka A., Yokoyama S.;
RL   Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10830953; DOI=10.1038/35012518;
RA   Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA   Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA   Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA   Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA   Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA   Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA   Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA   Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA   Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA   Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA   Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT   "The DNA sequence of human chromosome 21.";
RL   Nature 405:311-319(2000).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=PNS;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   TISSUE SPECIFICITY.
RX   PubMed=11169526;
RX   DOI=10.1002/1096-9896(2000)9999:9999<::aid-path743>3.0.co;2-t;
RA   Vaarala M.H., Porvari K.S., Kellokumpu S., Kyllonen A.P., Vihko P.T.;
RT   "Expression of transmembrane serine protease TMPRSS2 in mouse and human
RT   tissues.";
RL   J. Pathol. 193:134-140(2001).
RN   [10]
RP   FUNCTION.
RX   PubMed=15537383; DOI=10.1042/bj20041066;
RA   Wilson S., Greer B., Hooper J., Zijlstra A., Walker B., Quigley J.,
RA   Hawthorne S.;
RT   "The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in
RT   prostate cancer cells.";
RL   Biochem. J. 388:967-972(2005).
RN   [11]
RP   IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, AND GLYCOSYLATION.
RX   PubMed=20382709; DOI=10.2353/ajpath.2010.090665;
RA   Chen Y.W., Lee M.S., Lucht A., Chou F.P., Huang W., Havighurst T.C.,
RA   Kim K., Wang J.K., Antalis T.M., Johnson M.D., Lin C.Y.;
RT   "TMPRSS2, a serine protease expressed in the prostate on the apical surface
RT   of luminal epithelial cells and released into semen in prostasomes, is
RT   misregulated in prostate cancer cells.";
RL   Am. J. Pathol. 176:2986-2996(2010).
RN   [12]
RP   FUNCTION (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AUTOCATALYTIC
RP   CLEAVAGE, AND INTERACTION WITH ACE2.
RX   PubMed=21068237; DOI=10.1128/jvi.02062-10;
RA   Shulla A., Heald-Sargent T., Subramanya G., Zhao J., Perlman S.,
RA   Gallagher T.;
RT   "A transmembrane serine protease is linked to the severe acute respiratory
RT   syndrome coronavirus receptor and activates virus entry.";
RL   J. Virol. 85:873-882(2011).
RN   [13]
RP   FUNCTION (MICROBIAL INFECTION), AND TISSUE SPECIFICITY.
RX   PubMed=21325420; DOI=10.1128/jvi.02232-10;
RA   Glowacka I., Bertram S., Muller M.A., Allen P., Soilleux E., Pfefferle S.,
RA   Steffen I., Tsegaye T.S., He Y., Gnirss K., Niemeyer D., Schneider H.,
RA   Drosten C., Pohlmann S.;
RT   "Evidence that TMPRSS2 activates the severe acute respiratory syndrome
RT   coronavirus spike protein for membrane fusion and reduces viral control by
RT   the humoral immune response.";
RL   J. Virol. 85:4122-4134(2011).
RN   [14]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=23536651; DOI=10.1128/jvi.03372-12;
RA   Bertram S., Dijkman R., Habjan M., Heurich A., Gierer S., Glowacka I.,
RA   Welsch K., Winkler M., Schneider H., Hofmann-Winkler H., Thiel V.,
RA   Pohlmann S.;
RT   "TMPRSS2 activates the human coronavirus 229E for cathepsin-independent
RT   host cell entry and is expressed in viral target cells in the respiratory
RT   epithelium.";
RL   J. Virol. 87:6150-6160(2013).
RN   [15]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=23966399; DOI=10.1128/jvi.01490-13;
RA   Abe M., Tahara M., Sakai K., Yamaguchi H., Kanou K., Shirato K., Kawase M.,
RA   Noda M., Kimura H., Matsuyama S., Fukuhara H., Mizuta K., Maenaka K.,
RA   Ami Y., Esumi M., Kato A., Takeda M.;
RT   "TMPRSS2 is an activating protease for respiratory parainfluenza viruses.";
RL   J. Virol. 87:11930-11935(2013).
RN   [16]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=24027332; DOI=10.1128/jvi.01890-13;
RA   Shirato K., Kawase M., Matsuyama S.;
RT   "Middle East respiratory syndrome coronavirus infection mediated by the
RT   transmembrane serine protease TMPRSS2.";
RL   J. Virol. 87:12552-12561(2013).
RN   [17]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=24227843; DOI=10.1128/jvi.02202-13;
RA   Heurich A., Hofmann-Winkler H., Gierer S., Liepold T., Jahn O.,
RA   Poehlmann S.;
RT   "TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by
RT   TMPRSS2 augments entry driven by the severe acute respiratory syndrome
RT   coronavirus spike protein.";
RL   J. Virol. 88:1293-1307(2014).
RN   [18]
RP   FUNCTION, AND INDUCTION.
RX   PubMed=25122198; DOI=10.1158/2159-8290.cd-13-1010;
RA   Lucas J.M., Heinlein C., Kim T., Hernandez S.A., Malik M.S., True L.D.,
RA   Morrissey C., Corey E., Montgomery B., Mostaghel E., Clegg N., Coleman I.,
RA   Brown C.M., Schneider E.L., Craik C., Simon J.A., Bedalov A., Nelson P.S.;
RT   "The androgen-regulated protease TMPRSS2 activates a proteolytic cascade
RT   involving components of the tumor microenvironment and promotes prostate
RT   cancer metastasis.";
RL   Cancer Discov. 4:1310-1325(2014).
RN   [19]
RP   FUNCTION.
RX   PubMed=26018085; DOI=10.1158/0008-5472.can-14-3297;
RA   Ko C.J., Huang C.C., Lin H.Y., Juan C.P., Lan S.W., Shyu H.Y., Wu S.R.,
RA   Hsiao P.W., Huang H.P., Shun C.T., Lee M.S.;
RT   "Androgen-Induced TMPRSS2 activates matriptase and promotes extracellular
RT   matrix degradation, prostate cancer cell invasion, tumor growth, and
RT   metastasis.";
RL   Cancer Res. 75:2949-2960(2015).
RN   [20]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=32142651; DOI=10.1016/j.cell.2020.02.052;
RA   Hoffmann M., Kleine-Weber H., Schroeder S., Krueger N., Herrler T.,
RA   Erichsen S., Schiergens T.S., Herrler G., Wu N.H., Nitsche A.,
RA   Mueller M.A., Drosten C., Poehlmann S.;
RT   "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a
RT   clinically proven protease inhibitor.";
RL   Cell 181:1-10(2020).
RN   [21]
RP   VARIANTS MET-160; CYS-254; GLN-329 AND ASN-491.
RX   PubMed=17918732; DOI=10.1002/humu.20617;
RA   Guipponi M., Toh M.-Y., Tan J., Park D., Hanson K., Ballana E., Kwong D.,
RA   Cannon P.Z.F., Wu Q., Gout A., Delorenzi M., Speed T.P., Smith R.J.H.,
RA   Dahl H.-H.M., Petersen M., Teasdale R.D., Estivill X., Park W.J.,
RA   Scott H.S.;
RT   "An integrated genetic and functional analysis of the role of type II
RT   transmembrane serine proteases (TMPRSSs) in hearing loss.";
RL   Hum. Mutat. 29:130-141(2008).
CC   -!- FUNCTION: Plasma membrane-anchored serine protease that participates in
CC       proteolytic cascades of relevance for the normal physiologic function
CC       of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates
CC       several substrates that include pro-hepatocyte growth factor/HGF, the
CC       protease activated receptor-2/F2RL1 or matriptase/ST14 leading to
CC       extracellular matrix disruption and metastasis of prostate cancer cells
CC       (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition,
CC       activates trigeminal neurons and contribute to both spontaneous pain
CC       and mechanical allodynia (By similarity).
CC       {ECO:0000250|UniProtKB:Q9JIQ8, ECO:0000269|PubMed:15537383,
CC       ECO:0000269|PubMed:25122198, ECO:0000269|PubMed:26018085}.
CC   -!- FUNCTION: (Microbial infection) Facilitates human coronaviruses SARS-
CC       CoV and SARS-CoV-2 infections via two independent mechanisms,
CC       proteolytic cleavage of ACE2 receptor which promotes viral uptake, and
CC       cleavage of coronavirus spike glycoproteins which activates the
CC       glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651).
CC       Proteolytically cleaves and activates the spike glycoproteins of human
CC       coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and
CC       the fusion glycoproteins F0 of Sendai virus (SeV), human
CC       metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses
CC       (HPIV). Essential for spread and pathogenesis of influenza A virus
CC       (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and
CC       activation of hemagglutinin (HA) protein which is essential for viral
CC       infectivity. {ECO:0000269|PubMed:21068237, ECO:0000269|PubMed:21325420,
CC       ECO:0000269|PubMed:23536651, ECO:0000269|PubMed:23966399,
CC       ECO:0000269|PubMed:24027332, ECO:0000269|PubMed:24227843,
CC       ECO:0000269|PubMed:32142651}.
CC   -!- SUBUNIT: The catalytically active form interacts with ACE2.
CC       {ECO:0000269|PubMed:21068237}.
CC   -!- INTERACTION:
CC       O15393; Q9BYF1: ACE2; NbExp=3; IntAct=EBI-12549863, EBI-7730807;
CC       O15393-2; Q15848: ADIPOQ; NbExp=3; IntAct=EBI-12345267, EBI-10827839;
CC       O15393-2; Q86W74-2: ANKRD46; NbExp=3; IntAct=EBI-12345267, EBI-12109402;
CC       O15393-2; P29972: AQP1; NbExp=3; IntAct=EBI-12345267, EBI-745213;
CC       O15393-2; O95393: BMP10; NbExp=3; IntAct=EBI-12345267, EBI-3922513;
CC       O15393-2; Q12982: BNIP2; NbExp=3; IntAct=EBI-12345267, EBI-752094;
CC       O15393-2; Q12983: BNIP3; NbExp=3; IntAct=EBI-12345267, EBI-749464;
CC       O15393-2; Q6PL45-2: BRICD5; NbExp=3; IntAct=EBI-12345267, EBI-12244618;
CC       O15393-2; Q86Z23: C1QL4; NbExp=3; IntAct=EBI-12345267, EBI-12062109;
CC       O15393-2; O14523: C2CD2L; NbExp=3; IntAct=EBI-12345267, EBI-12822627;
CC       O15393-2; Q9BXR6: CFHR5; NbExp=3; IntAct=EBI-12345267, EBI-11579371;
CC       O15393-2; Q9BXN2-6: CLEC7A; NbExp=3; IntAct=EBI-12345267, EBI-11989440;
CC       O15393-2; Q9NWW5: CLN6; NbExp=3; IntAct=EBI-12345267, EBI-6165897;
CC       O15393-2; Q96FZ5: CMTM7; NbExp=3; IntAct=EBI-12345267, EBI-2807956;
CC       O15393-2; Q6PI25: CNIH2; NbExp=3; IntAct=EBI-12345267, EBI-12815321;
CC       O15393-2; Q8TBE1: CNIH3; NbExp=3; IntAct=EBI-12345267, EBI-12208021;
CC       O15393-2; Q4LDR2: CTXN3; NbExp=3; IntAct=EBI-12345267, EBI-12019274;
CC       O15393-2; Q07325: CXCL9; NbExp=3; IntAct=EBI-12345267, EBI-3911467;
CC       O15393-2; Q9BQA9: CYBC1; NbExp=3; IntAct=EBI-12345267, EBI-2680384;
CC       O15393-2; P81534: DEFB103B; NbExp=3; IntAct=EBI-12345267, EBI-12074168;
CC       O15393-2; P56851: EDDM3B; NbExp=3; IntAct=EBI-12345267, EBI-10215665;
CC       O15393-2; Q9UKR5: ERG28; NbExp=3; IntAct=EBI-12345267, EBI-711490;
CC       O15393-2; Q92520: FAM3C; NbExp=3; IntAct=EBI-12345267, EBI-2876774;
CC       O15393-2; Q96IV6: FAXDC2; NbExp=3; IntAct=EBI-12345267, EBI-12142299;
CC       O15393-2; P24593: IGFBP5; NbExp=3; IntAct=EBI-12345267, EBI-720480;
CC       O15393-2; Q6ZSS7: MFSD6; NbExp=3; IntAct=EBI-12345267, EBI-2858252;
CC       O15393-2; O75425: MOSPD3; NbExp=3; IntAct=EBI-12345267, EBI-12179105;
CC       O15393-2; Q9NZG7: NINJ2; NbExp=3; IntAct=EBI-12345267, EBI-10317425;
CC       O15393-2; Q9UHJ9-5: PGAP2; NbExp=3; IntAct=EBI-12345267, EBI-12092917;
CC       O15393-2; Q9Y342: PLLP; NbExp=3; IntAct=EBI-12345267, EBI-3919291;
CC       O15393-2; P26678: PLN; NbExp=3; IntAct=EBI-12345267, EBI-692836;
CC       O15393-2; P60201-2: PLP1; NbExp=3; IntAct=EBI-12345267, EBI-12188331;
CC       O15393-2; Q04941: PLP2; NbExp=4; IntAct=EBI-12345267, EBI-608347;
CC       O15393-2; Q13635-3: PTCH1; NbExp=3; IntAct=EBI-12345267, EBI-14199621;
CC       O15393-2; P53801: PTTG1IP; NbExp=3; IntAct=EBI-12345267, EBI-3906138;
CC       O15393-2; O00767: SCD; NbExp=4; IntAct=EBI-12345267, EBI-2684237;
CC       O15393-2; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-12345267, EBI-8652744;
CC       O15393-2; Q9Y6D0: SELENOK; NbExp=3; IntAct=EBI-12345267, EBI-9679163;
CC       O15393-2; P11686: SFTPC; NbExp=3; IntAct=EBI-12345267, EBI-10197617;
CC       O15393-2; P78382: SLC35A1; NbExp=3; IntAct=EBI-12345267, EBI-12870360;
CC       O15393-2; Q9NVC3: SLC38A7; NbExp=3; IntAct=EBI-12345267, EBI-10314552;
CC       O15393-2; B2RUZ4: SMIM1; NbExp=3; IntAct=EBI-12345267, EBI-12188413;
CC       O15393-2; O15400: STX7; NbExp=4; IntAct=EBI-12345267, EBI-3221827;
CC       O15393-2; Q9UNK0: STX8; NbExp=3; IntAct=EBI-12345267, EBI-727240;
CC       O15393-2; P17152: TMEM11; NbExp=3; IntAct=EBI-12345267, EBI-723946;
CC       O15393-2; A0PK00: TMEM120B; NbExp=3; IntAct=EBI-12345267, EBI-10171534;
CC       O15393-2; Q5BJH2-2: TMEM128; NbExp=3; IntAct=EBI-12345267, EBI-10694905;
CC       O15393-2; A2RU14: TMEM218; NbExp=3; IntAct=EBI-12345267, EBI-10173151;
CC       O15393-2; Q9H0R3: TMEM222; NbExp=3; IntAct=EBI-12345267, EBI-347385;
CC       O15393-2; Q8NBD8: TMEM229B; NbExp=3; IntAct=EBI-12345267, EBI-12195227;
CC       O15393-2; Q9BU79: TMEM243; NbExp=3; IntAct=EBI-12345267, EBI-12887458;
CC       O15393-2; Q9H2L4: TMEM60; NbExp=3; IntAct=EBI-12345267, EBI-2852148;
CC       O15393-2; Q9BSE2: TMEM79; NbExp=3; IntAct=EBI-12345267, EBI-8649725;
CC       O15393-2; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-12345267, EBI-12015604;
CC       O15393-2; Q8N661: TMEM86B; NbExp=3; IntAct=EBI-12345267, EBI-2548832;
CC       O15393-2; P01375: TNF; NbExp=3; IntAct=EBI-12345267, EBI-359977;
CC       O15393-2; Q5BVD1: TTMP; NbExp=5; IntAct=EBI-12345267, EBI-10243654;
CC       O15393-2; O00526: UPK2; NbExp=3; IntAct=EBI-12345267, EBI-10179682;
CC       O15393-2; O95183: VAMP5; NbExp=3; IntAct=EBI-12345267, EBI-10191195;
CC       O15393-2; Q9BQB6: VKORC1; NbExp=3; IntAct=EBI-12345267, EBI-6256462;
CC       O15393-2; O95159: ZFPL1; NbExp=3; IntAct=EBI-12345267, EBI-718439;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20382709,
CC       ECO:0000269|PubMed:21068237}; Single-pass type II membrane protein
CC       {ECO:0000269|PubMed:20382709, ECO:0000269|PubMed:21068237}.
CC   -!- SUBCELLULAR LOCATION: [Transmembrane protease serine 2 catalytic
CC       chain]: Secreted {ECO:0000269|PubMed:20382709}. Note=Activated by
CC       cleavage and secreted. {ECO:0000269|PubMed:11245484,
CC       ECO:0000269|PubMed:20382709}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O15393-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O15393-2; Sequence=VSP_045083;
CC   -!- TISSUE SPECIFICITY: Expressed in several tissues that comprise large
CC       populations of epithelial cells with the highest level of transcripts
CC       measured in the prostate gland. Expressed in type II pneumocytes in the
CC       lung (at protein level). Expressed strongly in small intestine. Also
CC       expressed in colon, stomach and salivary gland.
CC       {ECO:0000269|PubMed:11169526, ECO:0000269|PubMed:20382709,
CC       ECO:0000269|PubMed:21325420}.
CC   -!- INDUCTION: By androgenic hormones in vivo.
CC       {ECO:0000269|PubMed:25122198}.
CC   -!- PTM: Proteolytically processed; by an autocatalytic mechanism.
CC   -!- SIMILARITY: Belongs to the peptidase S1 family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00274}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/TMPRSS2ID42592ch21q22.html";
DR   EMBL; U75329; AAC51784.1; -; mRNA.
DR   EMBL; AF123453; AAD37117.1; -; mRNA.
DR   EMBL; AF270487; AAK29280.1; -; mRNA.
DR   EMBL; AK291813; BAF84502.1; -; mRNA.
DR   EMBL; AK296860; BAH12445.1; -; mRNA.
DR   EMBL; AK313338; BAG36142.1; -; mRNA.
DR   EMBL; AK222784; BAD96504.1; -; mRNA.
DR   EMBL; AP001610; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471079; EAX09597.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09598.1; -; Genomic_DNA.
DR   EMBL; BC051839; AAH51839.1; -; mRNA.
DR   CCDS; CCDS33564.1; -. [O15393-1]
DR   CCDS; CCDS54486.1; -. [O15393-2]
DR   RefSeq; NP_001128571.1; NM_001135099.1. [O15393-2]
DR   RefSeq; NP_005647.3; NM_005656.3. [O15393-1]
DR   RefSeq; XP_011528033.1; XM_011529731.2.
DR   SMR; O15393; -.
DR   BioGRID; 112968; 3.
DR   IntAct; O15393; 61.
DR   STRING; 9606.ENSP00000381588; -.
DR   BindingDB; O15393; -.
DR   ChEMBL; CHEMBL1795140; -.
DR   GuidetoPHARMACOLOGY; 2421; -.
DR   MEROPS; S01.247; -.
DR   GlyConnect; 1848; -.
DR   iPTMnet; O15393; -.
DR   PhosphoSitePlus; O15393; -.
DR   SwissPalm; O15393; -.
DR   BioMuta; TMPRSS2; -.
DR   jPOST; O15393; -.
DR   MassIVE; O15393; -.
DR   MaxQB; O15393; -.
DR   PaxDb; O15393; -.
DR   PeptideAtlas; O15393; -.
DR   PRIDE; O15393; -.
DR   ProteomicsDB; 31938; -.
DR   ProteomicsDB; 48634; -. [O15393-1]
DR   Antibodypedia; 2685; 293 antibodies.
DR   DNASU; 7113; -.
DR   Ensembl; ENST00000332149; ENSP00000330330; ENSG00000184012. [O15393-1]
DR   Ensembl; ENST00000398585; ENSP00000381588; ENSG00000184012. [O15393-2]
DR   Ensembl; ENST00000458356; ENSP00000391216; ENSG00000184012. [O15393-1]
DR   GeneID; 7113; -.
DR   KEGG; hsa:7113; -.
DR   UCSC; uc002yzj.4; human. [O15393-1]
DR   CTD; 7113; -.
DR   DisGeNET; 7113; -.
DR   EuPathDB; HostDB:ENSG00000184012.11; -.
DR   GeneCards; TMPRSS2; -.
DR   HGNC; HGNC:11876; TMPRSS2.
DR   HPA; ENSG00000184012; Tissue enhanced (intestine, pancreas, prostate).
DR   MIM; 602060; gene.
DR   neXtProt; NX_O15393; -.
DR   OpenTargets; ENSG00000184012; -.
DR   PharmGKB; PA36577; -.
DR   eggNOG; KOG3627; Eukaryota.
DR   eggNOG; COG5640; LUCA.
DR   GeneTree; ENSGT00940000155207; -.
DR   InParanoid; O15393; -.
DR   KO; K09633; -.
DR   OMA; YQPESLY; -.
DR   OrthoDB; 1314811at2759; -.
DR   PhylomeDB; O15393; -.
DR   TreeFam; TF351678; -.
DR   SIGNOR; O15393; -.
DR   BioGRID-ORCS; 7113; 1 hit in 786 CRISPR screens.
DR   ChiTaRS; TMPRSS2; human.
DR   GeneWiki; TMPRSS2; -.
DR   GenomeRNAi; 7113; -.
DR   Pharos; O15393; Tchem.
DR   PRO; PR:O15393; -.
DR   Proteomes; UP000005640; Chromosome 21.
DR   RNAct; O15393; protein.
DR   Bgee; ENSG00000184012; Expressed in mucosa of transverse colon and 141 other tissues.
DR   ExpressionAtlas; O15393; baseline and differential.
DR   Genevisible; O15393; HS.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0005044; F:scavenger receptor activity; IEA:InterPro.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
DR   GO; GO:0008236; F:serine-type peptidase activity; TAS:ProtInc.
DR   GO; GO:0046598; P:positive regulation of viral entry into host cell; IDA:UniProtKB.
DR   GO; GO:0016540; P:protein autoprocessing; IMP:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR   CDD; cd00112; LDLa; 1.
DR   CDD; cd00190; Tryp_SPc; 1.
DR   Gene3D; 3.10.250.10; -; 1.
DR   Gene3D; 4.10.400.10; -; 1.
DR   InterPro; IPR036055; LDL_receptor-like_sf.
DR   InterPro; IPR023415; LDLR_class-A_CS.
DR   InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR   InterPro; IPR009003; Peptidase_S1_PA.
DR   InterPro; IPR001314; Peptidase_S1A.
DR   InterPro; IPR001190; SRCR.
DR   InterPro; IPR017448; SRCR-like_dom.
DR   InterPro; IPR036772; SRCR-like_dom_sf.
DR   InterPro; IPR001254; Trypsin_dom.
DR   InterPro; IPR018114; TRYPSIN_HIS.
DR   InterPro; IPR033116; TRYPSIN_SER.
DR   Pfam; PF15494; SRCR_2; 1.
DR   Pfam; PF00089; Trypsin; 1.
DR   PRINTS; PR00722; CHYMOTRYPSIN.
DR   SMART; SM00192; LDLa; 1.
DR   SMART; SM00202; SR; 1.
DR   SMART; SM00020; Tryp_SPc; 1.
DR   SUPFAM; SSF50494; SSF50494; 1.
DR   SUPFAM; SSF56487; SSF56487; 1.
DR   SUPFAM; SSF57424; SSF57424; 1.
DR   PROSITE; PS01209; LDLRA_1; 1.
DR   PROSITE; PS50068; LDLRA_2; 1.
DR   PROSITE; PS50287; SRCR_2; 1.
DR   PROSITE; PS50240; TRYPSIN_DOM; 1.
DR   PROSITE; PS00134; TRYPSIN_HIS; 1.
DR   PROSITE; PS00135; TRYPSIN_SER; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Autocatalytic cleavage; Cell membrane;
KW   Disulfide bond; Glycoprotein; Hydrolase; Membrane; Polymorphism; Protease;
KW   Reference proteome; Secreted; Serine protease; Signal-anchor;
KW   Transmembrane; Transmembrane helix; Zymogen.
FT   CHAIN           1..255
FT                   /note="Transmembrane protease serine 2 non-catalytic chain"
FT                   /id="PRO_0000027855"
FT   CHAIN           256..492
FT                   /note="Transmembrane protease serine 2 catalytic chain"
FT                   /id="PRO_0000027856"
FT   TOPO_DOM        1..84
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        85..105
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        106..492
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          112..149
FT                   /note="LDL-receptor class A"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          150..242
FT                   /note="SRCR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT   DOMAIN          256..489
FT                   /note="Peptidase S1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   ACT_SITE        296
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        345
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        441
FT                   /note="Charge relay system"
FT   SITE            255..256
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000269|PubMed:11245484"
FT   CARBOHYD        213
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        249
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        113..126
FT                   /evidence="ECO:0000250"
FT   DISULFID        120..139
FT                   /evidence="ECO:0000250"
FT   DISULFID        133..148
FT                   /evidence="ECO:0000250"
FT   DISULFID        172..231
FT                   /evidence="ECO:0000250"
FT   DISULFID        185..241
FT                   /evidence="ECO:0000250"
FT   DISULFID        244..365
FT                   /note="Interchain (between non-catalytic and catalytic
FT                   chains)"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124,
FT                   ECO:0000255|PROSITE-ProRule:PRU00196, ECO:0000255|PROSITE-
FT                   ProRule:PRU00274"
FT   DISULFID        281..297
FT                   /evidence="ECO:0000250"
FT   DISULFID        410..426
FT                   /evidence="ECO:0000250"
FT   DISULFID        437..465
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         1
FT                   /note="M -> MPPAPPGGESGCEERGAAGHIEHSRYLSLLDAVDNSKM (in
FT                   isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_045083"
FT   VARIANT         160
FT                   /note="V -> M (in dbSNP:rs12329760)"
FT                   /evidence="ECO:0000269|PubMed:11414763,
FT                   ECO:0000269|PubMed:17918732, ECO:0000269|PubMed:9325052"
FT                   /id="VAR_027674"
FT   VARIANT         254
FT                   /note="S -> C"
FT                   /evidence="ECO:0000269|PubMed:17918732"
FT                   /id="VAR_038002"
FT   VARIANT         329
FT                   /note="E -> Q (in dbSNP:rs775137340)"
FT                   /evidence="ECO:0000269|PubMed:17918732,
FT                   ECO:0000269|PubMed:9325052"
FT                   /id="VAR_038003"
FT   VARIANT         449
FT                   /note="K -> N (in dbSNP:rs1056602)"
FT                   /id="VAR_011692"
FT   VARIANT         491
FT                   /note="D -> N (in dbSNP:rs779875214)"
FT                   /evidence="ECO:0000269|PubMed:17918732"
FT                   /id="VAR_038004"
FT   MUTAGEN         255
FT                   /note="R->Q: Loss of cleavage."
FT                   /evidence="ECO:0000269|PubMed:11245484"
FT   MUTAGEN         441
FT                   /note="S->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11245484"
FT   CONFLICT        26
FT                   /note="Y -> H (in Ref. 4; BAF84502)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        62
FT                   /note="N -> S (in Ref. 4; BAH12445)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        163
FT                   /note="S -> P (in Ref. 4; BAF84502)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        242
FT                   /note="I -> L (in Ref. 1; AAC51784)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        489..491
FT                   /note="RAD -> KAN (in Ref. 1; AAC51784)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   492 AA;  53859 MW;  C05B5531C8A311C7 CRC64;
     MALNSGSPPA IGPYYENHGY QPENPYPAQP TVVPTVYEVH PAQYYPSPVP QYAPRVLTQA
     SNPVVCTQPK SPSGTVCTSK TKKALCITLT LGTFLVGAAL AAGLLWKFMG SKCSNSGIEC
     DSSGTCINPS NWCDGVSHCP GGEDENRCVR LYGPNFILQV YSSQRKSWHP VCQDDWNENY
     GRAACRDMGY KNNFYSSQGI VDDSGSTSFM KLNTSAGNVD IYKKLYHSDA CSSKAVVSLR
     CIACGVNLNS SRQSRIVGGE SALPGAWPWQ VSLHVQNVHV CGGSIITPEW IVTAAHCVEK
     PLNNPWHWTA FAGILRQSFM FYGAGYQVEK VISHPNYDSK TKNNDIALMK LQKPLTFNDL
     VKPVCLPNPG MMLQPEQLCW ISGWGATEEK GKTSEVLNAA KVLLIETQRC NSRYVYDNLI
     TPAMICAGFL QGNVDSCQGD SGGPLVTSKN NIWWLIGDTS WGSGCAKAYR PGVYGNVMVF
     TDWIYRQMRA DG
//