ID TPA_HUMAN Reviewed; 562 AA. AC P00750; A8K022; B2R8E8; Q15103; Q503B0; Q6PJA5; Q7Z7N2; Q86YK8; AC Q9BU99; Q9BZW1; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 16-JAN-2019, entry version 245. DE RecName: Full=Tissue-type plasminogen activator; DE Short=t-PA; DE Short=t-plasminogen activator; DE Short=tPA; DE EC=3.4.21.68; DE AltName: INN=Alteplase; DE AltName: INN=Reteplase; DE Contains: DE RecName: Full=Tissue-type plasminogen activator chain A; DE Contains: DE RecName: Full=Tissue-type plasminogen activator chain B; DE Flags: Precursor; GN Name=PLAT; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Melanoma; RX PubMed=6337343; DOI=10.1038/301214a0; RA Pennica D., Holmes W.E., Kohr W.J., Harkins R.N., Vehar G.A., RA Ward C.A., Bennett W.F., Yelverton E., Seeburg P.H., Heyneker H.L., RA Goeddel D.V., Collen D.; RT "Cloning and expression of human tissue-type plasminogen activator RT cDNA in E. coli."; RL Nature 301:214-221(1983). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=6089198; DOI=10.1073/pnas.81.17.5355; RA Ny T., Elgh F., Lund B.; RT "The structure of the human tissue-type plasminogen activator gene: RT correlation of intron and exon structures to functional and structural RT domains."; RL Proc. Natl. Acad. Sci. U.S.A. 81:5355-5359(1984). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3009482; RA Friezner Degen S.J., Rajput B., Reich E.; RT "The human tissue plasminogen activator gene."; RL J. Biol. Chem. 261:6972-6985(1986). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=3090401; RA Harris T.J., Patel T., Marston F.A., Little S., Emtage J.S., RA Opdenakker G., Volckaert G., Rombauts W., Billiau A., Somer P.; RT "Cloning of cDNA coding for human tissue-type plasminogen activator RT and its expression in Escherichia coli."; RL Mol. Biol. Med. 3:279-292(1986). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2824147; DOI=10.1089/dna.1987.6.461; RA Reddy V.B., Garramone A.J., Sasak H., Wei C.-M., Watkins P., Galli J., RA Hsiung N.; RT "Expression of human uterine tissue-type plasminogen activator in RT mouse cells using BPV vectors."; RL DNA 6:461-472(1987). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Fetal lung; RX PubMed=3133640; DOI=10.1093/nar/16.12.5695; RA Sasaki H., Saito Y., Hayashi M., Otsuka K., Niwa M.; RT "Nucleotide sequence of the tissue-type plasminogen activator cDNA RT from human fetal lung cells."; RL Nucleic Acids Res. 16:5695-5695(1988). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Umbilical vein; RX PubMed=2107528; DOI=10.1093/nar/18.4.1086; RA Siebert P.D., Fong K.; RT "Variant tissue-type plasminogen activator (PLAT) cDNA obtained from RT human endothelial cells."; RL Nucleic Acids Res. 18:1086-1086(1990). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Dou D.; RT "A brain-type plasminogen activator."; RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Liu Y., Xu L., Zeng Y., He X.; RT "cDNA of tissue plasminogen activator."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Testis; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASP-34; SER-136; RP THR-146 AND TRP-164. RG SeattleSNPs variation discovery resource; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Brain, Placenta, and Skin; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [15] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-36. RX PubMed=3161893; RA Fisher R., Waller E.K., Grossi G., Thompson D., Tizard R., RA Schleuning W.-D.; RT "Isolation and characterization of the human tissue-type plasminogen RT activator structural gene including its 5' flanking region."; RL J. Biol. Chem. 260:11223-11230(1985). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 31-562. RX PubMed=1368681; DOI=10.1271/bbb1961.55.1225; RA Itagaki Y., Yasuda H., Morinaga T., Mitsuda S., Higashio K.; RT "Purification and characterization of tissue plasminogen activator RT secreted by human embryonic lung diploid fibroblasts, IMR-90 cells."; RL Agric. Biol. Chem. 55:1225-1232(1991). RN [17] RP PROTEIN SEQUENCE OF 33-52 AND 311-330. RC TISSUE=Melanoma; RX PubMed=6682760; DOI=10.1111/j.1432-1033.1983.tb07418.x; RA Wallen P., Pohl G., Bergsdorf N., Raanby M., Ny T., Joernvall H.; RT "Purification and characterization of a melanoma cell plasminogen RT activator."; RL Eur. J. Biochem. 132:681-686(1983). RN [18] RP PROTEIN SEQUENCE OF 36-562. RC TISSUE=Melanoma; RX PubMed=6433976; DOI=10.1021/bi00311a020; RA Pohl G., Kaellstroem M., Bergsdorf N., Wallen P., Joernvall H.; RT "Tissue plasminogen activator: peptide analyses confirm an indirectly RT derived amino acid sequence, identify the active site serine residue, RT establish glycosylation sites, and localize variant differences."; RL Biochemistry 23:3701-3707(1984). RN [19] RP NUCLEOTIDE SEQUENCE [MRNA] OF 251-358. RX PubMed=6572897; DOI=10.1073/pnas.80.2.349; RA Edlund T., Ny T., Raanby M., Heden L.-O., Palm G., Holmgren E., RA Josephson S.; RT "Isolation of cDNA sequences coding for a part of human tissue RT plasminogen activator."; RL Proc. Natl. Acad. Sci. U.S.A. 80:349-352(1983). RN [20] RP PARTIAL PROTEIN SEQUENCE, AND SIGNAL SEQUENCE CLEAVAGE SITE. RA Jalah R., Pavlakis G.N., Felber B.J.; RL Submitted (JUL-2007) to UniProtKB. RN [21] RP GLYCOSYLATION AT ASN-152; ASN-219 AND ASN-483, AND STRUCTURE OF RP CARBOHYDRATES. RX PubMed=2513186; DOI=10.1111/j.1432-1033.1989.tb15206.x; RA Pfeiffer G., Schmidt M., Strube K.-H., Geyer R.; RT "Carbohydrate structure of recombinant human uterine tissue RT plasminogen activator expressed in mouse epithelial cells."; RL Eur. J. Biochem. 186:273-286(1989). RN [22] RP GLYCOSYLATION AT THR-96. RX PubMed=1900431; DOI=10.1021/bi00223a004; RA Harris R.J., Leonard C.K., Guzzetta A.W., Spellman M.W.; RT "Tissue plasminogen activator has an O-linked fucose attached to RT threonine-61 in the epidermal growth factor domain."; RL Biochemistry 30:2311-2314(1991). RN [23] RP DISULFIDE BONDS IN KRINGLE 2 DOMAIN. RX PubMed=1645336; RA Vlahos C.J., Wilhelm O.G., Hassell T., Jaskunas S.R., Bang N.U.; RT "Disulfide pairing of the recombinant kringle-2 domain of tissue RT plasminogen activator produced in Escherichia coli."; RL J. Biol. Chem. 266:10070-10072(1991). RN [24] RP ACTIVITY REGULATION, AND HETERODIMER WITH SERPINA5. RX PubMed=10340997; DOI=10.1093/molehr/5.6.513; RA He S., Lin Y.L., Liu Y.X.; RT "Functionally inactive protein C inhibitor in seminal plasma may be RT associated with infertility."; RL Mol. Hum. Reprod. 5:513-519(1999). RN [25] RP INTERACTION WITH LRP1B. RX PubMed=11384978; DOI=10.1074/jbc.M102727200; RA Liu C.-X., Li Y., Obermoeller-McCormick L.M., Schwartz A.L., Bu G.; RT "The putative tumor suppressor LRP1B, a novel member of the low RT density lipoprotein (LDL) receptor family, exhibits both overlapping RT and distinct properties with the LDL receptor-related protein."; RL J. Biol. Chem. 276:28889-28896(2001). RN [26] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [27] RP STRUCTURE BY NMR OF KRINGLE 2. RX PubMed=2558718; DOI=10.1021/bi00450a016; RA Byeon I.-J.L., Kelley R.F., Llinas M.; RT "1H NMR structural characterization of a recombinant kringle 2 domain RT from human tissue-type plasminogen activator."; RL Biochemistry 28:9350-9360(1989). RN [28] RP STRUCTURE BY NMR OF KRINGLE 2. RX PubMed=1901789; DOI=10.1111/j.1432-1033.1991.tb15894.x; RA Byeon I.-J.L., Kelley R.F., Llinas M.; RT "Kringle-2 domain of the tissue-type plasminogen activator. 1H-NMR RT assignments and secondary structure."; RL Eur. J. Biochem. 197:155-165(1991). RN [29] RP STRUCTURE BY NMR OF KRINGLE 2. RX PubMed=1762144; DOI=10.1016/0022-2836(91)90592-T; RA Byeon I.-J.L., Llinas M.; RT "Solution structure of the tissue-type plasminogen activator kringle 2 RT domain complexed to 6-aminohexanoic acid an antifibrinolytic drug."; RL J. Mol. Biol. 222:1035-1051(1991). RN [30] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF KRINGLE 2. RX PubMed=1310033; DOI=10.1021/bi00116a037; RA de Vos A., Ultsch M.H., Kelley R.F., Padmanabhan K., Tulinskly A., RA Westbrook M.L., Kossiakof A.A.; RT "Crystal structure of the kringle 2 domain of tissue plasminogen RT activator at 2.4-A resolution."; RL Biochemistry 31:270-279(1992). RN [31] RP STRUCTURE BY NMR OF 38-85. RX PubMed=1602484; DOI=10.1016/0022-2836(92)90403-7; RA Downing A.K., Driscoll P.C., Harvey T.S., Dudgeon T.J., Smith B.O., RA Baron M., Campbell I.D.; RT "Solution structure of the fibrin binding finger domain of tissue-type RT plasminogen activator determined by 1H nuclear magnetic resonance."; RL J. Mol. Biol. 225:821-833(1992). RN [32] RP STRUCTURE BY NMR OF 36-126. RX PubMed=7582899; DOI=10.1016/S0969-2126(01)00217-9; RA Smith B.O., Downing A.K., Driscoll P.C., Dudgeon T.J., Campbell I.D.; RT "The solution structure and backbone dynamics of the fibronectin type RT I and epidermal growth factor-like pair of modules of tissue-type RT plasminogen activator."; RL Structure 3:823-833(1995). RN [33] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF CATALYTIC DOMAIN. RX PubMed=8613982; DOI=10.1006/jmbi.1996.0238; RA Lamba D., Bauer M., Huber R., Fischer S., Rudolph R., Kohnert U., RA Bode W.; RT "The 2.3 A crystal structure of the catalytic domain of recombinant RT two-chain human tissue-type plasminogen activator."; RL J. Mol. Biol. 258:117-135(1996). RN [34] RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF CATALYTIC DOMAIN. RX PubMed=9305622; DOI=10.1093/emboj/16.16.4797; RA Renatus M., Engh R.A., Stubbs M.T., Huber R., Fischer S., Kohnert U., RA Bode W.; RT "Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray RT crystal structure of single-chain human tPA."; RL EMBO J. 16:4797-4805(1997). CC -!- FUNCTION: Converts the abundant, but inactive, zymogen plasminogen CC to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By CC controlling plasmin-mediated proteolysis, it plays an important CC role in tissue remodeling and degradation, in cell migration and CC many other physiopathological events. Plays a direct role in CC facilitating neuronal migration. CC -!- CATALYTIC ACTIVITY: CC Reaction=Specific cleavage of Arg-|-Val bond in plasminogen to CC form plasmin.; EC=3.4.21.68; CC -!- ACTIVITY REGULATION: Inhibited by SERPINA5. CC {ECO:0000269|PubMed:10340997}. CC -!- SUBUNIT: Heterodimer of chain A and chain B held by a disulfide CC bond. Forms a heterodimer with SERPINA5. Binds to fibrin with high CC affinity. This interaction leads to an increase in the catalytic CC efficiency of the enzyme between 100-fold and 1000-fold, due to an CC increase in affinity for plasminogen. Similarly, binding to CC heparin increases the activation of plasminogen. Binds to annexin CC A2, cytokeratin-8, fibronectin and laminin. Binds to mannose CC receptor and the low-density lipoprotein receptor-related protein CC (LRP1); these proteins are involved in TPA clearance. Yet CC unidentified interactions on endothelial cells and vascular smooth CC muscle cells (VSMC) lead to a 100-fold stimulation of plasminogen CC activation. In addition, binding to VSMC reduces TPA inhibition by CC PAI-1 by 30-fold. Binds LRP1B; binding is followed by CC internalization and degradation. CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=Long; CC IsoId=P00750-1; Sequence=Displayed; CC Name=2; Synonyms=Short; CC IsoId=P00750-2; Sequence=VSP_005411, VSP_005412; CC Note=May be produced at very low levels due to a premature stop CC codon in the mRNA, leading to nonsense-mediated mRNA decay.; CC Name=3; CC IsoId=P00750-3; Sequence=VSP_015957; CC Note=No experimental confirmation available.; CC Name=4; Synonyms=Neonatal; CC IsoId=P00750-4; Sequence=VSP_028029, VSP_028030; CC Note=No experimental confirmation available.; CC -!- TISSUE SPECIFICITY: Synthesized in numerous tissues (including CC tumors) and secreted into most extracellular body fluids, such as CC plasma, uterine fluid, saliva, gingival crevicular fluid, tears, CC seminal fluid, and milk. CC -!- DOMAIN: Both FN1 and one of the kringle domains are required for CC binding to fibrin. CC -!- DOMAIN: Both FN1 and EGF-like domains are important for binding to CC LRP1. CC -!- DOMAIN: The FN1 domain mediates binding to annexin A2. CC -!- DOMAIN: The second kringle domain is implicated in binding to CC cytokeratin-8 and to the endothelial cell surface binding site. CC -!- PTM: The single chain, almost fully active enzyme, can be further CC processed into a two-chain fully active form by a cleavage after CC Arg-310 catalyzed by plasmin, tissue kallikrein or factor Xa. CC -!- PTM: Differential cell-specific N-linked glycosylation gives rise CC to two glycoforms, type I (glycosylated at Asn-219) and type II CC (not glycosylated at Asn-219). The single chain type I glycoform CC is less readily converted into the two-chain form by plasmin, and CC the two-chain type I glycoform has a lower activity than the two- CC chain type II glycoform in the presence of fibrin. CC {ECO:0000269|PubMed:1900431}. CC -!- PTM: N-glycosylation of Asn-152; the bound oligomannosidic glycan CC is involved in the interaction with the mannose receptor. CC {ECO:0000269|PubMed:1900431}. CC -!- PTM: Characterization of O-linked glycan was studied in Bowes CC melanoma cell line. {ECO:0000269|PubMed:1900431}. CC -!- DISEASE: Note=Increased activity of TPA results in increased CC fibrinolysis of fibrin blood clots that is associated with CC excessive bleeding. Defective release of TPA results in CC hypofibrinolysis that can lead to thrombosis or embolism. CC {ECO:0000269|PubMed:1762144}. CC -!- PHARMACEUTICAL: Available under the names Activase (Genentech) and CC Retavase (Centocor and Roche) [Retavase is a fragment of TPA that CC contains kringle 2 and the protease domain; it was also known as CC BM 06.022]. Used in Acute Myocardial Infarction (AMI), in Acute CC Ischemic Stroke (AIS) and Pulmonary Embolism (PE) to initiate CC fibrinolysis. CC -!- SIMILARITY: Belongs to the peptidase S1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00274}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tissue plasminogen activator CC entry; CC URL="https://en.wikipedia.org/wiki/Tissue_plasminogen_Activator"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/plat/"; CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and CC polymorphism database; CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=PLAT"; CC -!- WEB RESOURCE: Name=Activase; Note=Clinical information on CC Activase; CC URL="https://www.activase.com/"; CC -!- WEB RESOURCE: Name=Chiesi; Note=Clinical information on Retavase; CC URL="https://chiesiusa.com/products/retavase-2/"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; L00153; AAB59510.1; -; Genomic_DNA. DR EMBL; L00141; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00142; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00143; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00144; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00145; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00146; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00147; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00148; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00149; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00150; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; L00151; AAB59510.1; JOINED; Genomic_DNA. DR EMBL; K03021; AAA98809.1; -; Genomic_DNA. DR EMBL; M15518; AAA60111.1; -; mRNA. DR EMBL; M18182; AAA36800.1; -; mRNA. DR EMBL; X07393; CAA30302.1; -; mRNA. DR EMBL; X13097; CAA31489.1; -; mRNA. DR EMBL; AF260825; AAK11956.1; -; mRNA. DR EMBL; AY221101; AAO34406.1; -; mRNA. DR EMBL; AK289387; BAF82076.1; -; mRNA. DR EMBL; AK290575; BAF83264.1; -; mRNA. DR EMBL; AK313342; BAG36145.1; -; mRNA. DR EMBL; BT007060; AAP35709.1; -; mRNA. DR EMBL; AY291060; AAP34246.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63235.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63233.1; -; Genomic_DNA. DR EMBL; BC002795; AAH02795.3; -; mRNA. DR EMBL; BC007231; AAH07231.1; -; mRNA. DR EMBL; BC013968; AAH13968.3; -; mRNA. DR EMBL; BC018636; AAH18636.3; -; mRNA. DR EMBL; BC095403; AAH95403.1; -; mRNA. DR EMBL; M11890; AAA61213.1; -; Genomic_DNA. DR EMBL; M11889; AAA61213.1; JOINED; Genomic_DNA. DR EMBL; D01096; BAA00881.1; -; mRNA. DR EMBL; V00570; CAA23833.1; -; mRNA. DR CCDS; CCDS6126.1; -. [P00750-1] DR CCDS; CCDS6127.1; -. [P00750-3] DR PIR; A94004; UKHUT. DR PIR; I38098; I38098. DR RefSeq; NP_000921.1; NM_000930.4. [P00750-1] DR RefSeq; NP_001306118.1; NM_001319189.1. DR RefSeq; NP_127509.1; NM_033011.3. [P00750-3] DR UniGene; Hs.491582; -. DR PDB; 1A5H; X-ray; 2.90 A; A/B=311-562, C/D=298-304. DR PDB; 1BDA; X-ray; 3.35 A; A/B=298-562. DR PDB; 1PK2; NMR; -; A=209-298. DR PDB; 1PML; X-ray; 2.38 A; A/B/C=213-298. DR PDB; 1RTF; X-ray; 2.30 A; B=311-562. DR PDB; 1TPG; NMR; -; A=36-126. DR PDB; 1TPK; X-ray; 2.40 A; A/B/C=211-298. DR PDB; 1TPM; NMR; -; A=36-85. DR PDB; 1TPN; NMR; -; A=36-85. DR PDB; 5BRR; X-ray; 3.16 A; E=311-562. DR PDBsum; 1A5H; -. DR PDBsum; 1BDA; -. DR PDBsum; 1PK2; -. DR PDBsum; 1PML; -. DR PDBsum; 1RTF; -. DR PDBsum; 1TPG; -. DR PDBsum; 1TPK; -. DR PDBsum; 1TPM; -. DR PDBsum; 1TPN; -. DR PDBsum; 5BRR; -. DR ProteinModelPortal; P00750; -. DR SMR; P00750; -. DR BioGrid; 111343; 40. DR ComplexPortal; CPX-494; tPA-PAI-1 complex. DR ELM; P00750; -. DR IntAct; P00750; 2. DR MINT; P00750; -. DR STRING; 9606.ENSP00000220809; -. DR BindingDB; P00750; -. DR ChEMBL; CHEMBL1873; -. DR DrugBank; DB07684; 5-(DIMETHYLAMINO)-2-NAPHTHALENESULFONIC ACID. DR DrugBank; DB00513; Aminocaproic Acid. DR DrugBank; DB06404; C1 Esterase Inhibitor (Human). DR DrugBank; DB09228; C1 Esterase Inhibitor (Recombinant). DR DrugBank; DB01050; Ibuprofen. DR DrugBank; DB01088; Iloprost. DR DrugBank; DB00013; Urokinase. DR GuidetoPHARMACOLOGY; 2392; -. DR MEROPS; S01.232; -. DR GlyConnect; 503; -. DR GlyConnect; 504; -. DR GlyConnect; 603; -. DR iPTMnet; P00750; -. DR PhosphoSitePlus; P00750; -. DR UniCarbKB; P00750; -. DR BioMuta; PLAT; -. DR DMDM; 137119; -. DR EPD; P00750; -. DR jPOST; P00750; -. DR MaxQB; P00750; -. DR PaxDb; P00750; -. DR PeptideAtlas; P00750; -. DR PRIDE; P00750; -. DR ProteomicsDB; 51281; -. DR ProteomicsDB; 51282; -. [P00750-2] DR ProteomicsDB; 51283; -. [P00750-3] DR ProteomicsDB; 51284; -. [P00750-4] DR DNASU; 5327; -. DR Ensembl; ENST00000220809; ENSP00000220809; ENSG00000104368. [P00750-1] DR Ensembl; ENST00000352041; ENSP00000270188; ENSG00000104368. [P00750-3] DR Ensembl; ENST00000429089; ENSP00000392045; ENSG00000104368. [P00750-1] DR GeneID; 5327; -. DR KEGG; hsa:5327; -. DR UCSC; uc003xos.3; human. [P00750-1] DR CTD; 5327; -. DR DisGeNET; 5327; -. DR EuPathDB; HostDB:ENSG00000104368.17; -. DR GeneCards; PLAT; -. DR HGNC; HGNC:9051; PLAT. DR HPA; CAB009335; -. DR HPA; HPA003412; -. DR MalaCards; PLAT; -. DR MIM; 173370; gene. DR neXtProt; NX_P00750; -. DR OpenTargets; ENSG00000104368; -. DR Orphanet; 480528; Lethal hydranencephaly-diaphragmatic hernia syndrome. DR PharmGKB; PA33381; -. DR eggNOG; KOG3627; Eukaryota. DR eggNOG; COG5640; LUCA. DR GeneTree; ENSGT00940000158930; -. DR HOVERGEN; HBG008633; -. DR InParanoid; P00750; -. DR KO; K01343; -. DR OMA; PLVCMKD; -. DR OrthoDB; 1314811at2759; -. DR PhylomeDB; P00750; -. DR TreeFam; TF329901; -. DR BRENDA; 3.4.21.68; 2681. DR Reactome; R-HSA-186797; Signaling by PDGF. DR Reactome; R-HSA-75205; Dissolution of Fibrin Clot. DR SIGNOR; P00750; -. DR ChiTaRS; PLAT; human. DR EvolutionaryTrace; P00750; -. DR GeneWiki; Tissue_plasminogen_activator; -. DR GenomeRNAi; 5327; -. DR PMAP-CutDB; P00750; -. DR PRO; PR:P00750; -. DR Proteomes; UP000005640; Chromosome 8. DR Bgee; ENSG00000104368; Expressed in 217 organ(s), highest expression level in metanephric glomerulus. DR ExpressionAtlas; P00750; baseline and differential. DR Genevisible; P00750; HS. DR GO; GO:0045177; C:apical part of cell; IEA:Ensembl. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0051219; F:phosphoprotein binding; IPI:AgBase. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:BHF-UCL. DR GO; GO:0005102; F:signaling receptor binding; IPI:AgBase. DR GO; GO:0007596; P:blood coagulation; TAS:ProtInc. DR GO; GO:0006464; P:cellular protein modification process; TAS:ProtInc. DR GO; GO:0042730; P:fibrinolysis; TAS:Reactome. DR GO; GO:0045861; P:negative regulation of proteolysis; IDA:BHF-UCL. DR GO; GO:0031639; P:plasminogen activation; IDA:UniProtKB. DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; IBA:GO_Central. DR GO; GO:0006508; P:proteolysis; IBA:GO_Central. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0014909; P:smooth muscle cell migration; IBA:GO_Central. DR GO; GO:0099183; P:trans-synaptic signaling by BDNF, modulating synaptic transmission; IEA:Ensembl. DR CDD; cd00061; FN1; 1. DR CDD; cd00108; KR; 2. DR CDD; cd00190; Tryp_SPc; 1. DR Gene3D; 2.40.20.10; -; 2. DR InterPro; IPR013032; EGF-like_CS. DR InterPro; IPR000742; EGF-like_dom. DR InterPro; IPR000083; Fibronectin_type1. DR InterPro; IPR000001; Kringle. DR InterPro; IPR013806; Kringle-like. DR InterPro; IPR018056; Kringle_CS. DR InterPro; IPR038178; Kringle_sf. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR001314; Peptidase_S1A. DR InterPro; IPR026280; Tissue_plasm_act. DR InterPro; IPR034811; tPA. DR InterPro; IPR001254; Trypsin_dom. DR InterPro; IPR018114; TRYPSIN_HIS. DR InterPro; IPR033116; TRYPSIN_SER. DR PANTHER; PTHR44617; PTHR44617; 1. DR Pfam; PF00008; EGF; 1. DR Pfam; PF00039; fn1; 1. DR Pfam; PF00051; Kringle; 2. DR Pfam; PF00089; Trypsin; 1. DR PIRSF; PIRSF001145; Tissue_plasm_act; 1. DR PRINTS; PR00722; CHYMOTRYPSIN. DR SMART; SM00058; FN1; 1. DR SMART; SM00130; KR; 2. DR SMART; SM00020; Tryp_SPc; 1. DR SUPFAM; SSF50494; SSF50494; 1. DR SUPFAM; SSF57440; SSF57440; 2. DR PROSITE; PS00022; EGF_1; 1. DR PROSITE; PS01186; EGF_2; 1. DR PROSITE; PS50026; EGF_3; 1. DR PROSITE; PS01253; FN1_1; 1. DR PROSITE; PS51091; FN1_2; 1. DR PROSITE; PS00021; KRINGLE_1; 2. DR PROSITE; PS50070; KRINGLE_2; 2. 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 3D-structure; Alternative splicing; KW Cleavage on pair of basic residues; Complete proteome; KW Direct protein sequencing; Disulfide bond; EGF-like domain; KW Glycoprotein; Hydrolase; Kringle; Pharmaceutical; KW Plasminogen activation; Polymorphism; Protease; Reference proteome; KW Repeat; Secreted; Serine protease; Signal; Zymogen. FT SIGNAL 1 22 {ECO:0000269|Ref.20}. FT PROPEP 23 32 {ECO:0000269|PubMed:6682760}. FT /FTId=PRO_0000028348. FT PROPEP 33 35 Removed by plasmin. FT {ECO:0000269|PubMed:6433976}. FT /FTId=PRO_0000028349. FT CHAIN 36 562 Tissue-type plasminogen activator. FT /FTId=PRO_0000028350. FT CHAIN 36 310 Tissue-type plasminogen activator chain FT A. FT /FTId=PRO_0000028351. FT CHAIN 311 562 Tissue-type plasminogen activator chain FT B. FT /FTId=PRO_0000028352. FT DOMAIN 39 81 Fibronectin type-I. {ECO:0000255|PROSITE- FT ProRule:PRU00478}. FT DOMAIN 82 120 EGF-like. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 127 208 Kringle 1. {ECO:0000255|PROSITE- FT ProRule:PRU00121}. FT DOMAIN 215 296 Kringle 2. {ECO:0000255|PROSITE- FT ProRule:PRU00121}. FT DOMAIN 311 561 Peptidase S1. {ECO:0000255|PROSITE- FT ProRule:PRU00274}. FT REGION 42 52 Important for binding to annexin A2. FT ACT_SITE 357 357 Charge relay system. FT {ECO:0000305|PubMed:8613982}. FT ACT_SITE 406 406 Charge relay system. FT {ECO:0000305|PubMed:8613982}. FT ACT_SITE 513 513 Charge relay system. FT {ECO:0000305|PubMed:8613982}. FT SITE 102 102 Important for binding to LRP1. FT SITE 253 253 Not glycosylated. FT SITE 464 464 Important for single-chain activity. FT SITE 512 512 Important for single-chain activity. FT CARBOHYD 96 96 O-linked (Fuc) threonine. FT {ECO:0000269|PubMed:1900431}. FT /FTId=CAR_000029. FT CARBOHYD 152 152 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:2513186}. FT CARBOHYD 219 219 N-linked (GlcNAc...) asparagine; partial. FT {ECO:0000269|PubMed:2513186}. FT /FTId=CAR_000030. FT CARBOHYD 483 483 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:2513186}. FT /FTId=CAR_000031. FT DISULFID 41 71 {ECO:0000269|PubMed:1645336}. FT DISULFID 69 78 {ECO:0000269|PubMed:1645336}. FT DISULFID 86 97 {ECO:0000269|PubMed:1645336}. FT DISULFID 91 108 {ECO:0000269|PubMed:1645336}. FT DISULFID 110 119 {ECO:0000269|PubMed:1645336}. FT DISULFID 127 208 {ECO:0000250}. FT DISULFID 148 190 {ECO:0000250}. FT DISULFID 179 203 {ECO:0000250}. FT DISULFID 215 296 {ECO:0000269|PubMed:1645336}. FT DISULFID 236 278 {ECO:0000269|PubMed:1645336}. FT DISULFID 267 291 {ECO:0000269|PubMed:1645336}. FT DISULFID 299 430 Interchain (between A and B chains). FT {ECO:0000255|PROSITE-ProRule:PRU00076, FT ECO:0000255|PROSITE-ProRule:PRU00121, FT ECO:0000255|PROSITE-ProRule:PRU00274, FT ECO:0000255|PROSITE-ProRule:PRU00478, FT ECO:0000269|PubMed:1645336}. FT DISULFID 342 358 {ECO:0000250}. FT DISULFID 350 419 {ECO:0000250}. FT DISULFID 444 519 {ECO:0000250}. FT DISULFID 476 492 {ECO:0000250}. FT DISULFID 509 537 {ECO:0000250}. FT VAR_SEQ 1 40 MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRGARSYQVI FT -> MAS (in isoform 4). FT {ECO:0000303|Ref.8}. FT /FTId=VSP_028029. FT VAR_SEQ 39 85 VICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCH FT SVPVKS -> G (in isoform 3). FT {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334}. FT /FTId=VSP_015957. FT VAR_SEQ 79 208 Missing (in isoform 4). FT {ECO:0000303|Ref.8}. FT /FTId=VSP_028030. FT VAR_SEQ 269 291 NPDGDAKPWCHVLKNRRLTWEYC -> TGRSVSSPATASMR FT PCPLSIRSG (in isoform 2). FT {ECO:0000303|PubMed:2107528}. FT /FTId=VSP_005411. FT VAR_SEQ 292 562 Missing (in isoform 2). FT {ECO:0000303|PubMed:2107528}. FT /FTId=VSP_005412. FT VARIANT 34 34 A -> D (in dbSNP:rs8178733). FT {ECO:0000269|Ref.12}. FT /FTId=VAR_020181. FT VARIANT 136 136 R -> S (in dbSNP:rs8178747). FT {ECO:0000269|Ref.12}. FT /FTId=VAR_038732. FT VARIANT 146 146 A -> T (in dbSNP:rs8178748). FT {ECO:0000269|Ref.12}. FT /FTId=VAR_038733. FT VARIANT 164 164 R -> W (in dbSNP:rs2020921). FT {ECO:0000269|Ref.12}. FT /FTId=VAR_011783. FT CONFLICT 93 93 N -> T (in Ref. 2; AAB59510). FT {ECO:0000305}. FT CONFLICT 159 160 KP -> NA (in Ref. 7; CAA31489). FT {ECO:0000305}. FT CONFLICT 247 247 K -> N (in Ref. 9; AAO34406). FT {ECO:0000305}. FT CONFLICT 283 283 N -> S (in Ref. 14; AAH95403). FT {ECO:0000305}. FT CONFLICT 333 334 RR -> EE (in Ref. 8; AAK11956). FT {ECO:0000305}. FT CONFLICT 389 389 V -> C (in Ref. 8; AAK11956). FT {ECO:0000305}. FT STRAND 41 43 {ECO:0000244|PDB:1TPM}. FT STRAND 44 46 {ECO:0000244|PDB:1TPG}. FT STRAND 48 50 {ECO:0000244|PDB:1TPM}. FT STRAND 55 59 {ECO:0000244|PDB:1TPG}. FT STRAND 61 64 {ECO:0000244|PDB:1TPG}. FT STRAND 66 70 {ECO:0000244|PDB:1TPG}. FT STRAND 72 74 {ECO:0000244|PDB:1TPG}. FT STRAND 77 81 {ECO:0000244|PDB:1TPM}. FT STRAND 83 85 {ECO:0000244|PDB:1TPG}. FT STRAND 96 104 {ECO:0000244|PDB:1TPG}. FT STRAND 106 109 {ECO:0000244|PDB:1TPG}. FT STRAND 115 118 {ECO:0000244|PDB:1TPG}. FT STRAND 221 223 {ECO:0000244|PDB:1PK2}. FT STRAND 229 233 {ECO:0000244|PDB:1PK2}. FT HELIX 242 244 {ECO:0000244|PDB:1PML}. FT STRAND 248 250 {ECO:0000244|PDB:1PML}. FT STRAND 251 253 {ECO:0000244|PDB:1PK2}. FT HELIX 256 259 {ECO:0000244|PDB:1PML}. FT STRAND 262 264 {ECO:0000244|PDB:1PML}. FT STRAND 277 282 {ECO:0000244|PDB:1PML}. FT STRAND 285 291 {ECO:0000244|PDB:1PML}. FT STRAND 309 311 {ECO:0000244|PDB:1BDA}. FT STRAND 312 316 {ECO:0000244|PDB:1RTF}. FT HELIX 319 321 {ECO:0000244|PDB:1RTF}. FT STRAND 325 331 {ECO:0000244|PDB:1RTF}. FT STRAND 338 346 {ECO:0000244|PDB:1RTF}. FT STRAND 348 354 {ECO:0000244|PDB:1RTF}. FT HELIX 356 359 {ECO:0000244|PDB:1RTF}. FT HELIX 365 367 {ECO:0000244|PDB:1RTF}. FT STRAND 368 373 {ECO:0000244|PDB:1RTF}. FT STRAND 375 379 {ECO:0000244|PDB:1RTF}. FT STRAND 385 394 {ECO:0000244|PDB:1RTF}. FT TURN 400 402 {ECO:0000244|PDB:1RTF}. FT STRAND 408 412 {ECO:0000244|PDB:1RTF}. FT STRAND 415 417 {ECO:0000244|PDB:1RTF}. FT STRAND 423 425 {ECO:0000244|PDB:5BRR}. FT STRAND 443 449 {ECO:0000244|PDB:1RTF}. FT STRAND 451 453 {ECO:0000244|PDB:1BDA}. FT STRAND 464 470 {ECO:0000244|PDB:1RTF}. FT HELIX 473 475 {ECO:0000244|PDB:1RTF}. FT TURN 478 483 {ECO:0000244|PDB:1RTF}. FT STRAND 490 494 {ECO:0000244|PDB:1RTF}. FT STRAND 499 501 {ECO:0000244|PDB:1A5H}. FT STRAND 516 521 {ECO:0000244|PDB:1RTF}. FT STRAND 524 533 {ECO:0000244|PDB:1RTF}. FT STRAND 535 538 {ECO:0000244|PDB:1RTF}. FT STRAND 544 548 {ECO:0000244|PDB:1RTF}. FT HELIX 549 552 {ECO:0000244|PDB:1RTF}. FT HELIX 553 559 {ECO:0000244|PDB:1RTF}. SQ SEQUENCE 562 AA; 62917 MW; B7EC9B1A5E3FDC4D CRC64; MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARSYQVI CRDEKTQMIY QQHQSWLRPV LRSNRVEYCW CNSGRAQCHS VPVKSCSEPR CFNGGTCQQA LYFSDFVCQC PEGFAGKCCE IDTRATCYED QGISYRGTWS TAESGAECTN WNSSALAQKP YSGRRPDAIR LGLGNHNYCR NPDRDSKPWC YVFKAGKYSS EFCSTPACSE GNSDCYFGNG SAYRGTHSLT ESGASCLPWN SMILIGKVYT AQNPSAQALG LGKHNYCRNP DGDAKPWCHV LKNRRLTWEY CDVPSCSTCG LRQYSQPQFR IKGGLFADIA SHPWQAAIFA KHRRSPGERF LCGGILISSC WILSAAHCFQ ERFPPHHLTV ILGRTYRVVP GEEEQKFEVE KYIVHKEFDD DTYDNDIALL QLKSDSSRCA QESSVVRTVC LPPADLQLPD WTECELSGYG KHEALSPFYS ERLKEAHVRL YPSSRCTSQH LLNRTVTDNM LCAGDTRSGG PQANLHDACQ GDSGGPLVCL NDGRMTLVGI ISWGLGCGQK DVPGVYTKVT NYLDWIRDNM RP //