ID   TPA_RAT                 Reviewed;         559 AA.
AC   P19637;
DT   01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1991, sequence version 2.
DT   04-NOV-2026, entry version 196.
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   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   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3148445; DOI=10.1089/dna.1988.7.671;
RA   Ny T., Leonardsson G., Hsueh A.J.W.;
RT   "Cloning and characterization of a cDNA for rat tissue-type plasminogen
RT   activator.";
RL   DNA 7:671-677(1988).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=2105315; DOI=10.1016/s0021-9258(19)39934-x;
RA   Feng P., Ohlsson M., Ny T.;
RT   "The structure of the TATA-less rat tissue-type plasminogen activator gene.
RT   Species-specific sequence divergences in the promoter predict differences
RT   in regulation of gene expression.";
RL   J. Biol. Chem. 265:2022-2027(1990).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pituitary;
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   [4]
RP   FUNCTION.
RX   PubMed=1515147; DOI=10.1002/mrd.1080320106;
RA   Zhang X., Rutledge J., Khamsi F., Armstrong D.T.;
RT   "Release of tissue-type plasminogen activator by activated rat eggs and its
RT   possible role in the zona reaction.";
RL   Mol. Reprod. Dev. 32:28-32(1992).
CC   -!- FUNCTION: Converts the abundant, but inactive, zymogen plasminogen to
CC       plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By
CC       controlling plasmin-mediated proteolysis, it plays an important role in
CC       tissue remodeling and degradation, in cell migration and many other
CC       physiopathological events. During oocyte activation, plays a role in
CC       cortical granule reaction in the zona reaction, which contributes to
CC       the block to polyspermy (PubMed:1515147). {ECO:0000269|PubMed:1515147}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Specific cleavage of Arg-|-Val bond in plasminogen to form
CC         plasmin.; EC=3.4.21.68;
CC   -!- ACTIVITY REGULATION: Inhibited by SERPINA5 (By similarity). Inhibited
CC       by SERPINE1 (By similarity). {ECO:0000250|UniProtKB:P00750}.
CC   -!- SUBUNIT: Heterodimer of chain A and chain B held by a disulfide bond.
CC       Binds to fibrin with high affinity. This interaction leads to an
CC       increase in the catalytic efficiency of the enzyme due to an increase
CC       in affinity for plasminogen. Similarly, binding to heparin increases
CC       the activation of plasminogen. Binds to annexin A2, cytokeratin-8,
CC       fibronectin and laminin. Binds to mannose receptor and the low-density
CC       lipoprotein receptor-related protein (LRP1); these proteins are
CC       involved in TPA clearance. Binds LRP1B; binding is followed by
CC       internalization and degradation. Forms heterodimer with SERPINA5 (By
CC       similarity). Interacts with SERPINE1 (By similarity). In complex with
CC       SERPINE1, interacts with SORL1 (By similarity). {ECO:0000250,
CC       ECO:0000250|UniProtKB:P00750}.
CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC   -!- DOMAIN: Both FN1 and one of the kringle domains are required for
CC       binding to fibrin. {ECO:0000250}.
CC   -!- DOMAIN: Both FN1 and EGF-like domains are important for binding to
CC       LRP1. {ECO:0000250}.
CC   -!- DOMAIN: The FN1 domain mediates binding to annexin A2. {ECO:0000250}.
CC   -!- DOMAIN: The second kringle domain is implicated in binding to
CC       cytokeratin-8 and to the endothelial cell surface binding site.
CC       {ECO:0000250}.
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 Arg-
CC       308 catalyzed by plasmin, tissue kallikrein or factor Xa.
CC   -!- SIMILARITY: Belongs to the peptidase S1 family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00274}.
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DR   EMBL; M23697; AAA41812.1; -; mRNA.
DR   EMBL; M31197; AAA42261.1; -; Genomic_DNA.
DR   EMBL; M31185; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31186; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31187; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31188; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31189; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31190; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31191; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31192; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31193; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31194; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31195; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; M31196; AAA42261.1; JOINED; Genomic_DNA.
DR   EMBL; BC061565; AAH61565.1; -; mRNA.
DR   PIR; A35029; A35029.
DR   RefSeq; NP_037283.2; NM_013151.3.
DR   RefSeq; XP_063131168.1; XM_063275098.1.
DR   SMR; P19637; -.
DR   IntAct; P19637; 1.
DR   STRING; 10116.ENSRNOP00000025764; -.
DR   ChEMBL; CHEMBL6195701; -.
DR   MEROPS; S01.232; -.
DR   GlyCosmos; P19637; 2 sites, No reported glycans.
DR   GlyGen; P19637; 2 sites.
DR   PhosphoSitePlus; P19637; -.
DR   PaxDb; 10116-ENSRNOP00000025764; -.
DR   jPOST; P19637; -.
DR   Ensembl; ENSRNOT00060048368; ENSRNOP00060040283; ENSRNOG00060027808.
DR   GeneID; 25692; -.
DR   KEGG; rno:25692; -.
DR   UCSC; RGD:3342; rat.
DR   CTD; 5327; -.
DR   VEuPathDB; HostDB:ENSRNOG00000019018; -.
DR   AGR; RGD:3342; -.
DR   RGD; 3342; Plat.
DR   eggNOG; KOG3627; Eukaryota.
DR   HOGENOM; CLU_006842_18_4_1; -.
DR   InParanoid; P19637; -.
DR   OrthoDB; 6020543at2759; -.
DR   PhylomeDB; P19637; -.
DR   BRENDA; 3.4.21.68; 5301.
DR   Reactome; R-RNO-186797; Signaling by PDGF.
DR   Reactome; R-RNO-75205; Dissolution of Fibrin Clot.
DR   PRO; PR:P19637; -.
DR   Bgee; ENSRNOG00000019018; Expressed in ovary and 20 other cell types or tissues.
DR   CDD; cd00054; EGF_CA; 1.
DR   CDD; cd00108; KR; 2.
DR   CDD; cd00190; Tryp_SPc; 1.
DR   FunFam; 2.10.70.10:FF:000043; Plasminogen activator; 1.
DR   FunFam; 2.10.25.10:FF:000483; Tissue-type plasminogen activator; 1.
DR   FunFam; 2.40.10.10:FF:000003; Transmembrane serine protease 3; 1.
DR   FunFam; 2.40.20.10:FF:000001; Urokinase-type plasminogen activator; 2.
DR   Gene3D; 2.10.70.10; Complement Module, domain 1; 1.
DR   Gene3D; 2.10.25.10; Laminin; 1.
DR   Gene3D; 2.40.20.10; Plasminogen Kringle 4; 2.
DR   Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2.
DR   InterPro; IPR000742; EGF.
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; IPR050127; Serine_Proteases_S1.
DR   InterPro; IPR026280; Tissue_plasm_act.
DR   InterPro; IPR001254; Trypsin_dom.
DR   InterPro; IPR018114; TRYPSIN_HIS.
DR   InterPro; IPR033116; TRYPSIN_SER.
DR   PANTHER; PTHR24264:SF42; TISSUE-TYPE PLASMINOGEN ACTIVATOR; 1.
DR   PANTHER; PTHR24264; TRYPSIN-RELATED; 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   PRINTS; PR00018; KRINGLE.
DR   SMART; SM00181; EGF; 1.
DR   SMART; SM00058; FN1; 1.
DR   SMART; SM00130; KR; 2.
DR   SMART; SM00020; Tryp_SPc; 1.
DR   SUPFAM; SSF57603; FnI-like domain; 1.
DR   SUPFAM; SSF57440; Kringle-like; 2.
DR   SUPFAM; SSF50494; Trypsin-like serine proteases; 1.
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.
DR   GO; GO:0045177; C:apical part of cell; ISO:RGD.
DR   GO; GO:0009986; C:cell surface; ISO:RGD.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005576; C:extracellular region; IDA:RGD.
DR   GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR   GO; GO:0098992; C:neuronal dense core vesicle; IDA:SynGO.
DR   GO; GO:0099544; C:perisynaptic space; IDA:SynGO.
DR   GO; GO:0098794; C:postsynapse; IDA:SynGO.
DR   GO; GO:0098685; C:Schaffer collateral - CA1 synapse; ISO:RGD.
DR   GO; GO:0030141; C:secretory granule; ISO:RGD.
DR   GO; GO:0097180; C:serine protease inhibitor complex; ISO:RGD.
DR   GO; GO:0051219; F:phosphoprotein binding; ISO:RGD.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; ISO:RGD.
DR   GO; GO:0005102; F:signaling receptor binding; ISO:RGD.
DR   GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEP:RGD.
DR   GO; GO:0071372; P:cellular response to follicle-stimulating hormone stimulus; IEP:RGD.
DR   GO; GO:0071373; P:cellular response to luteinizing hormone stimulus; IEP:RGD.
DR   GO; GO:0045861; P:negative regulation of proteolysis; ISO:RGD.
DR   GO; GO:0031639; P:plasminogen activation; IDA:RGD.
DR   GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; ISO:RGD.
DR   GO; GO:0060468; P:prevention of polyspermy; IDA:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; ISO:RGD.
DR   GO; GO:0048167; P:regulation of synaptic plasticity; IEP:RGD.
DR   GO; GO:0051591; P:response to cAMP; IEP:RGD.
DR   GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR   GO; GO:0001666; P:response to hypoxia; ISO:RGD.
DR   GO; GO:0014909; P:smooth muscle cell migration; ISO:RGD.
DR   GO; GO:0035249; P:synaptic transmission, glutamatergic; IMP:RGD.
DR   GO; GO:0099183; P:trans-synaptic signaling by BDNF, modulating synaptic transmission; ISO:RGD.
DR   Proteomes; UP000002494; Chromosome 16.
DR   AlphaFoldDB; P19637; -.
DR   FunCoup; P19637; 655.
PE   2: Evidence at transcript level;
KW   Cleavage on pair of basic residues; Disulfide bond; EGF-like domain;
KW   Glycoprotein; Hydrolase; Kringle; Plasminogen activation; Protease;
KW   Reference proteome; Repeat; Secreted; Serine protease; Signal; Zymogen.
FT   SIGNAL          1..17
FT                   /evidence="ECO:0000255"
FT   PROPEP          18..29
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000028357"
FT   PROPEP          30..32
FT                   /note="Removed by plasmin"
FT                   /id="PRO_0000285917"
FT   CHAIN           33..559
FT                   /note="Tissue-type plasminogen activator"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000028358"
FT   CHAIN           33..308
FT                   /note="Tissue-type plasminogen activator chain A"
FT                   /id="PRO_0000028359"
FT   CHAIN           309..559
FT                   /note="Tissue-type plasminogen activator chain B"
FT                   /id="PRO_0000028360"
FT   DOMAIN          36..78
FT                   /note="Fibronectin type-I"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00478"
FT   DOMAIN          79..117
FT                   /note="EGF-like"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DOMAIN          124..205
FT                   /note="Kringle 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00121"
FT   DOMAIN          213..294
FT                   /note="Kringle 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00121"
FT   DOMAIN          309..558
FT                   /note="Peptidase S1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00274"
FT   REGION          39..49
FT                   /note="Important for binding to annexin A2"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        355
FT                   /note="Charge relay system"
FT   ACT_SITE        404
FT                   /note="Charge relay system"
FT   ACT_SITE        510
FT                   /note="Charge relay system"
FT   SITE            99
FT                   /note="Important for binding to LRP1"
FT                   /evidence="ECO:0000250"
FT   SITE            462
FT                   /note="Important for single-chain activity"
FT                   /evidence="ECO:0000250"
FT   SITE            509
FT                   /note="Important for single-chain activity"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        149
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        481
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        38..68
FT                   /evidence="ECO:0000250"
FT   DISULFID        66..75
FT                   /evidence="ECO:0000250"
FT   DISULFID        83..94
FT                   /evidence="ECO:0000250"
FT   DISULFID        88..105
FT                   /evidence="ECO:0000250"
FT   DISULFID        107..116
FT                   /evidence="ECO:0000250"
FT   DISULFID        124..205
FT                   /evidence="ECO:0000250"
FT   DISULFID        145..187
FT                   /evidence="ECO:0000250"
FT   DISULFID        176..200
FT                   /evidence="ECO:0000250"
FT   DISULFID        213..294
FT                   /evidence="ECO:0000250"
FT   DISULFID        234..276
FT                   /evidence="ECO:0000250"
FT   DISULFID        265..289
FT                   /evidence="ECO:0000250"
FT   DISULFID        297..428
FT                   /note="Interchain (between A and B chains)"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT                   ECO:0000255|PROSITE-ProRule:PRU00121, ECO:0000255|PROSITE-
FT                   ProRule:PRU00274, ECO:0000255|PROSITE-ProRule:PRU00478"
FT   DISULFID        340..356
FT                   /evidence="ECO:0000250"
FT   DISULFID        348..417
FT                   /evidence="ECO:0000250"
FT   DISULFID        442..516
FT                   /evidence="ECO:0000250"
FT   DISULFID        474..490
FT                   /evidence="ECO:0000250"
FT   DISULFID        506..534
FT                   /evidence="ECO:0000250"
FT   CONFLICT        380
FT                   /note="E -> K (in Ref. 1; AAA41812)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   559 AA;  62903 MW;  7DBD3809C1D1C921 CRC64;
     MKGELLCVLL LCGVAFTLPD QGIHRRFRRG ARSYRATCRD EQTQTTYQQH QSWLRPMLRG
     NRVEYCRCNS GLAQCHSVPV RSCSEPRCFN GGTCQQALYF SDFVCQCPDG FVGKRCDIDT
     RATCFEGQGI TYRGTWSTAE NGAECINWNS SALSQKPYSA RRPNAIKLGL GNHNYCRNPD
     RDVKPWCYVF KAGKYTTEFC STPACPKGPT EDCYVGKGVT YRGTHSFTTS KASCLPWNSM
     ILIGKTYTAW RANSQALGLG RHNYCRNPDG DAKPWCHVMK DRKLTWEYCD MSPCSTCGLR
     QYKQPQFRIK GGLFTDITSH PWQAAIFVKN KRSPGERFLC GGVLISSCWV LSAAHCFVER
     FPPHHLKVVL GRTYRVVPGE EEQTFEIEKY IVHKEFDDDT YDNDIALLQL RSDSSQCAQE
     SSSVGTACLP DPDVQLPDWT ECELSGYGKH EASSPFFSDR LKEAHVRLYP SSRCTSQHLF
     NKTITSNMLC AGDTRTGGNQ DVHDACQGDS GGPLVCMIDK RMTLLGIISW GLGCGQKDVP
     GIYTKVTNYL NWIQDNMKQ
//