Tissue factor

F3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AHW, 1BOY, 1DAN, 1FAK, 1J9C, 1JPS, 1O5D, 1TFH, 1UJ3, 1W0Y, 1W2K, 1WQV, 1WSS, 1WTG, 1WUN, 1WV7, 1Z6J, 2A2Q, 2AEI, 2AER, 2B7D, 2B8O, 2C4F, 2CEF, 2CEH, 2CEZ, 2CFJ, 2EC9, 2F9B, 2FIR, 2FLB, 2HFT, 2PUQ, 2ZP0, 2ZWL, 2ZZU, 3ELA, 3TH2, 3TH3, 3TH4, 4IBL, 4M7L, 4Z6A, 4ZMA, 4YLQ, 2FLR
Identifiers
Aliases	F3, CD142, TF, TFA, coagulation factor III, tissue factor
External IDs	OMIM: 134390 MGI: 88381 HomoloGene: 1511 GeneCards: F3
Gene ontology Molecular function • protein binding • cytokine receptor activity • phospholipid binding • serine-type endopeptidase activity • protease binding Cellular component • integral component of membrane • membrane • extracellular matrix • intrinsic component of external side of plasma membrane • plasma membrane • extracellular region • extracellular exosome • extracellular fluid • cell surface Biological process • hemostasis • positive regulation of protein kinase B signaling • positive regulation of endothelial cell proliferation • cytokine-mediated signaling pathway • positive regulation of cell migration • activation of blood coagulation via clotting cascade • positive regulation of platelet-derived growth factor receptor signaling pathway • positive regulation of angiogenesis • blood coagulation, extrinsic pathway • activation of plasma proteins involved in acute inflammatory response • activation of cysteine-type endopeptidase activity involved in apoptotic process • positive regulation of positive chemotaxis • blood coagulation • protein processing Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2152	14066
Ensembl	ENSG00000117525	ENSMUSG00000028128
UniProt	P13726	P20352
RefSeq (mRNA)	NM_001993 NM_001178096	NM_010171
RefSeq (protein)	NP_001171567.1 NP_001984.1	NP_034301.3
Location (UCSC)	Chr 1: 94.53 – 94.54 Mb	Chr 3: 121.72 – 121.74 Mb
PubMed search	[1]	[2]
Wikidata

Tissue factor, also called platelet tissue factor, factor III, thromboplastin, or CD142 is a protein present in subendothelial tissue and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X - the tissue factor pathway. In doing so it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.

Function

This gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described.^[3] In addition to the membrane-bound tissue factor, soluble form of tissue factor was also found which results from alternatively spliced tissue factor mRNA transcripts, in which exon 5 is absent and exon 4 is spliced directly to exon 6.^[4][5]

Coagulation

The coagulation cascade.

TF is the cell surface receptor for the serine protease factor VIIa.

The best known function of tissue factor is its role in blood coagulation. The complex of TF with factor VIIa activates factor IX and catalyzes the conversion of the inactive protease factor X into the active protease factor Xa.

Together with factor VIIa, tissue factor forms the tissue factor or extrinsic pathway of coagulation. This is opposed to the intrinsic (amplification) pathway which involves both activated factor IX and factor VIII. Both pathways lead to the activation of factor X (the common pathway) which combines with activated factor V in the presence of calcium and phospholipid to produce thrombin (thromboplastin activity).

Cytokine signaling

TF is related to a protein family known as the cytokine receptor class II family. The members of this receptor family are activated by cytokines. Cytokines are small proteins that can influence the behavior of white blood cells. Binding of VIIa to TF has also been found to start signaling processes inside the cell. The signaling function of TF/VIIa plays a role in angiogenesis and apoptosis.

Structure

Tissue factor belongs to the cytokine receptor protein superfamily and consists of three domains:^[6]

1. an extracellular domain, which consists of two fibronectin type III modules whose hydrophobic cores merge in the domain-domain interface. This serves as a (probably rigid) template for factor VIIa binding.
2. a transmembrane domain.
3. a cytosolic domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.

Note that one of factor VIIa's domains, GLA domain, binds in the presence of calcium to negatively charged phospholipids, and this binding greatly enhances factor VIIa binding to tissue factor.

Tissue distribution

Some cells release TF in response to blood vessel damage (see next paragraph) and some do only in response to inflammatory mediators (endothelial cells/macrophages).

TF is expressed by cells which are normally not exposed to flowing blood such as sub-endothelial cells (e.g. smooth muscle cells) and cells surrounding blood vessels (e.g. fibroblasts). This can change when the blood vessel is damaged by for example physical injury or rupture of atherosclerotic plaques. Exposure of TF expressing cells during injury allows the complex formation of TF with factor VII. Factor VII and TF form an equal molar complex in the presence of calcium ions and this leads to the activation of factor VII on a membrane surface.

The inner surface of the blood vessel consists of endothelial cells. Endothelial cells do not express TF except when they are exposed to inflammatory molecules such as tumor necrosis factor-alpha (TNF-alpha). Another cell type that expresses TF on the cell surface in inflammatory conditions is the monocyte (a white blood cell).

Thromboplastin

Historically, thromboplastin was a lab reagent, usually derived from placental sources, used to assay prothrombin times (PT time). Thromboplastin, by itself, could activate the extrinsic coagulation pathway. When manipulated in the laboratory, a derivative could be created called partial thromboplastin. Partial thromboplastin was used to measure the intrinsic pathway. This test is called the aPTT, or activated partial thromboplastin time. It was not until much later that the subcomponents of thromboplastin and partial thromboplastin were identified. Thromboplastin is the combination of both phospholipids and tissue factor, both needed in the activation of the extrinsic pathway, and partial thromboplastin is just phospholipids without tissue factor. Tissue factor is not needed to activate the intrinsic pathway.

Interactions

Tissue factor has been shown to interact with Factor VII.^[7][8]

Additional images

• 
  Tissue factor
• 
  Blood plasma after the addition of tissue factor

See also

• hemostasis

References

Further reading

External links

• Online Mendelian Inheritance in Man (OMIM) 134390
• PDB Molecule of the Month Tissue factor - March 2006

PDB gallery
1ahw: A COMPLEX OF EXTRACELLULAR DOMAIN OF TISSUE FACTOR WITH AN INHIBITORY FAB (5G9)  1boy: EXTRACELLULAR REGION OF HUMAN TISSUE FACTOR  1dan: COMPLEX OF ACTIVE SITE INHIBITED HUMAN BLOOD COAGULATION FACTOR VIIA WITH HUMAN RECOMBINANT SOLUBLE TISSUE FACTOR  1fak: HUMAN TISSUE FACTOR COMPLEXED WITH COAGULATION FACTOR VIIA INHIBITED WITH A BPTI-MUTANT  1j9c: Crystal Structure of tissue factor-factor VIIa complex  1jps: Crystal structure of tissue factor in complex with humanized Fab D3h44  1o5d: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)  1tfh: EXTRACELLULAR DOMAIN OF HUMAN TISSUE FACTOR  1uj3: Crystal structure of a humanized Fab fragment of anti-tissue-factor antibody in complex with tissue factor  1w0y: TF7A_3771 COMPLEX  1w2k: TF7A_4380 COMPLEX  1wqv: Human Factor Viia-Tissue Factor Complexed with propylsulfonamide-D-Thr-Met-p-aminobenzamidine  1wss: Human Factor Viia-Tissue Factor in Complex with peprid mimetic inhibitor that has two charge groups in P2 and P4  1wtg: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-biphenylalanine-Gln-p-aminobenzamidine  1wun: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-Trp-Gln-p-aminobenzamidine  1wv7: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-5-propoxy-Trp-Gln-p-aminobenzamidine  1z6j: Crystal Structure of a ternary complex of Factor VIIa/Tissue Factor/Pyrazinone Inhibitor  2a2q: Complex of Active-site Inhibited Human Coagulation Factor VIIa with Human Soluble Tissue Factor in the Presence of Ca2+, Mg2+, Na+, and Zn2+  2aei: Crystal structure of a ternary complex of factor VIIa/tissue factor and 2-[[6-[3-(aminoiminomethyl)phenoxy]-3,5-difluro-4-[(1-methyl-3-phenylpropyl)amino]-2-pyridinyl]oxy]-benzoic acid  2aer: Crystal Structure of Benzamidine-Factor VIIa/Soluble Tissue Factor complex.  2b7d: Factor VIIa Inhibitors: Chemical Optimization, Preclinical Pharmacokinetics, Pharmacodynamics, and Efficacy in a Baboon Thrombosis Model  2b8o: Crystal Structure of Glu-Gly-Arg-Chloromethyl Ketone-Factor VIIa/Soluble Tissue Factor Complex  2c4f: CRYSTAL STRUCTURE OF FACTOR VII.STF COMPLEXED WITH PD0297121  2f9b: Discovery of Novel Heterocyclic Factor VIIa Inhibitors  2fir: Crystal structure of DFPR-VIIa/sTF  2flb: Discovery of a Novel Hydroxy Pyrazole Based Factor IXa Inhibitor  2flr: Novel 5-Azaindole Factor VIIa Inhibitors  2hft: THE CRYSTAL STRUCTURE OF THE EXTRACELLULAR DOMAIN OF HUMAN TISSUE FACTOR AT 1.7 ANGSTROMS RESOLUTION  2puq: Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor