MGP Database

MGP002310

UniProt Annotations

Entry Information

Gene Name	plasminogen activator, tissue
Protein Entry	TPA_HUMAN
UniProt ID	P00750
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative splicing; Named isoforms=4; Name=1; Synonyms=Long; IsoId=P00750-1; Sequence=Displayed; Name=2; Synonyms=Short; IsoId=P00750-2; Sequence=VSP_005411, VSP_005412; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.; Name=3; IsoId=P00750-3; Sequence=VSP_015957; Note=No experimental confirmation available.; Name=4; Synonyms=Neonatal; IsoId=P00750-4; Sequence=VSP_028029, VSP_028030; Note=No experimental confirmation available.;
Catalytic Activity	Specific cleavage of Arg-\|-Val bond in plasminogen to form plasmin.
Disease	Note=Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism.
Domain	Both FN1 and EGF-like domains are important for binding to LRP1.
Domain	Both FN1 and one of the kringle domains are required for binding to fibrin.
Domain	The FN1 domain mediates binding to annexin A2.
Domain	The second kringle domain is implicated in binding to cytokeratin-8 and to the endothelial cell surface binding site.
Enzyme Regulation	Inhibited by SERPINA5. {ECO:0000269\|PubMed:10340997}.
Function	Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration.
Pharmaceutical	Available under the names Activase (Genentech) and Retavase (Centocor and Roche) [Retavase is a fragment of TPA that contains kringle 2 and the protease domain; it was also known as BM 06.022]. Used in Acute Myocardial Infarction (AMI), in Acute Ischemic Stroke (AIS) and Pulmonary Embolism (PE) to initiate fibrinolysis.
Ptm	Characterization of O-linked glycan was studied in Bowes melanoma cell line. {ECO:0000269\|PubMed:1900431}.
Ptm	Differential cell-specific N-linked glycosylation gives rise to two glycoforms, type I (glycosylated at Asn-219) and type II (not glycosylated at Asn-219). The single chain type I glycoform is less readily converted into the two-chain form by plasmin, and the two-chain type I glycoform has a lower activity than the two- chain type II glycoform in the presence of fibrin. {ECO:0000269\|PubMed:1900431}.
Ptm	N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor. {ECO:0000269\|PubMed:1900431}.
Ptm	The single chain, almost fully active enzyme, can be further processed into a two-chain fully active form by a cleavage after Arg-310 catalyzed by plasmin, tissue kallikrein or factor Xa.
Similarity	Belongs to the peptidase S1 family. {ECO:0000255\|PROSITE-ProRule:PRU00274}.
Similarity	Contains 1 EGF-like domain. {ECO:0000255\|PROSITE- ProRule:PRU00076}.
Similarity	Contains 1 fibronectin type-I domain. {ECO:0000255\|PROSITE-ProRule:PRU00478}.
Similarity	Contains 1 peptidase S1 domain. {ECO:0000255\|PROSITE- ProRule:PRU00274}.
Similarity	Contains 2 kringle domains. {ECO:0000255\|PROSITE- ProRule:PRU00121}.
Subcellular Location	Secreted, extracellular space.
Subunit	Heterodimer of chain A and chain B held by a disulfide bond. Forms a heterodimer with SERPINA5. Binds to fibrin with high affinity. This interaction leads to an increase in the catalytic efficiency of the enzyme between 100-fold and 1000-fold, due to an increase in affinity for plasminogen. Similarly, binding to heparin increases the activation of plasminogen. Binds to annexin A2, cytokeratin-8, fibronectin and laminin. Binds to mannose receptor and the low-density lipoprotein receptor-related protein (LRP1); these proteins are involved in TPA clearance. Yet unidentified interactions on endothelial cells and vascular smooth muscle cells (VSMC) lead to a 100-fold stimulation of plasminogen activation. In addition, binding to VSMC reduces TPA inhibition by PAI-1 by 30-fold. Binds LRP1B; binding is followed by internalization and degradation.
Tissue Specificity	Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk.
Web Resource	Name=Activase; Note=Clinical information on Activase; URL="http://www.gene.com/gene/products/information/cardiovascular/activase/insert.jsp#pharmacology";
Web Resource	Name=Retavase; Note=Clinical information on Retavase; URL="http://www.retavase.com/pdf/Retavase_PI.pdf";
Web Resource	Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/plat/";
Web Resource	Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=PLAT";
Web Resource	Name=Wikipedia; Note=Tissue plasminogen activator entry; URL="http://en.wikipedia.org/wiki/Tissue_plasminogen_Activator";