tissue-type plasminogen activator; t-PA; t-plasminogen activator; tPA (PLAT)

Function

• relatively fibrin-selective plasminogen activator
  • converts plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen
  • by controlling plasmin-mediated proteolysis, plays a role in tissue remodeling & degradation, in cell migration & many other physiopathological events
  • minimizes systemic lytic states
  • play a direct role in facilitating neuronal migration
  • inhibited by SERPINA5
  • 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
  • differential cell-specific N-linked glycosylation gives rise to two glycoforms, type 1 (glycosylated at Asn-219) & type1 (not glycosylated at Asn-219)
  • the single chain type 1 glycoform is less readily converted into the two-chain form by plasmin, & the two-chain type 1 glycoform has a lower activity than the two-chain type 2 glycoform in the presence of fibrin
  • N-glycosylation of Asn-152; the bound oligomannosidic glycan is involved in the interaction with the mannose receptor characterization of O-linked glycan was studied in Bowes melanoma cell line
  • heterodimer of chain A & chain B held by a disulfide bond.
  • forms 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 & 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 & laminin
  • binds to mannose receptor & LRP1 leading to TPA clearance
  • interactions on endothelial cells & vascular smooth muscle cells lead to a 100-fold stimulation of plasminogen activation
  • binding to vascular smooth muscle cells reduces TPA inhibition by PAI-1 by 30-fold
  • binds LRP1B; binding is followed by internalization & degradation

Structure

• both FN1 domains & one of the kringle domains are required for binding to fibrin
• both FN1 domains & EGF-like domains are important for binding to LRP1
• the FN1 domain mediates binding to annexin A2
• the second kringle domain is implicated in binding to cytokeratin-8 & to the endothelial cell surface binding site
• belongs to the peptidase S1 family
• contains 1 EGF-like domain
• contains 1 fibronectin type-1 domain (FN1 domain)
• contains 2 kringle domains
• contains 1 peptidase S1 domain

Compartment

secreted, extracellular space

Alternative splicing

• named isoforms=4
  • at least 1 isoform may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay

Expression

• synthesized in numerous tissues (including tumors) & secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, & milk

Pathology

• 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

Pharmacology

• vailable under the names alteplase (Activase) (Genentech) & reteplase (Retavase) (Centocor & Roche)
• reteplase (Retavase) is a fragment of TPA that contains kringle 2 & the protease domain
• see recombinant tissue plasminogen activator

More general terms

• plasminogen activator
• plasma protein
• glycoprotein

More specific terms

• recombinant tissue plasminogen activator (TPA, t-PA, rt-PA,)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5327
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5327
• OMIM: https://mirror.omim.org/entry/173370
• UniProt: http://www.uniprot.org/uniprot/P00750.html