Plasminogen activator inhibitor-1

Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1
PAI-1 in complex with the SMB domain of Vitronectin PDB 1OC0
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A7C, 1B3K, 1C5G, 1DB2, 1DVM, 1DVN, 1LJ5, 1OC0, 3CVM, 3EOX, 3PB1, 3Q02, 3Q03, 3R4L, 3UT3, 4AQH, 4G8O, 4G8R, 4IC0, 9PAI
Identifiers
Symbols	SERPINE1 ; PAI; PAI-1; PAI1; PLANH1
External IDs	OMIM: 173360 MGI: 97608 HomoloGene: 68070 ChEMBL: 3475 GeneCards: SERPINE1 Gene
Gene ontology Molecular function • protease binding • serine-type endopeptidase inhibitor activity • receptor binding • protein binding Cellular component • extracellular region • extracellular space • plasma membrane • extracellular matrix • platelet alpha granule lumen Biological process • chronological cell aging • angiogenesis • platelet degranulation • transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • transforming growth factor beta receptor signaling pathway • blood coagulation • gene expression • regulation of receptor activity • negative regulation of plasminogen activation • negative regulation of endopeptidase activity • negative regulation of smooth muscle cell migration • platelet activation • positive regulation of blood coagulation • negative regulation of blood coagulation • extracellular matrix organization • negative regulation of cell migration • positive regulation of interleukin-8 production • negative regulation of cell adhesion mediated by integrin • positive regulation of leukotriene production involved in inflammatory response • regulation of cell proliferation • fibrinolysis • positive regulation of angiogenesis • positive regulation of transcription from RNA polymerase II promoter • positive regulation of receptor-mediated endocytosis • positive regulation of inflammatory response • defense response to Gram-negative bacterium • negative regulation of fibrinolysis • negative regulation of vascular wound healing • negative regulation of wound healing • cellular response to lipopolysaccharide • positive regulation of monocyte chemotaxis • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • negative regulation of smooth muscle cell-matrix adhesion • negative regulation of endothelial cell apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5054	18787
Ensembl	ENSG00000106366	ENSMUSG00000037411
UniProt	P05121	n/a
RefSeq (mRNA)	NM_000602	NM_008871
RefSeq (protein)	NP_000593	NP_032897
Location (UCSC)	Chr 7: 100.77 – 100.78 Mb	Chr 5: 137.06 – 137.07 Mb
PubMed search

Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene.

PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). It is a serine protease inhibitor (serpin) protein (SERPINE1).

The other PAI, plasminogen activator inhibitor-2 (PAI-2) is secreted by the placenta and only present in significant amounts during pregnancy. In addition, protease nexin acts as an inhibitor of tPA and urokinase. PAI-1, however, is the main inhibitor of the plasminogen activators.

Genetics

The PAI-1 gene is SERPINE1, located on chromosome 7 (7q21.3-q22). There is a common polymorphism known as 4G/5G in the promoter region. The 5G allele is slightly less transcriptionally active than the 4G.

Function

PAI-1 is mainly produced by the endothelium (cells lining blood vessels), but is also secreted by other tissue types, such as adipose tissue.

PAI-1 inhibits the serine proteases tPA and uPA/urokinase, and hence is an inhibitor of fibrinolysis, the physiological process that degrades blood clots.

PAI-1 inhibits the activity of matrix metalloproteinases, which play a crucial role in invasion of malignant cells across the basal lamina.

Role in disease

Congenital deficiency of PAI-1 has been reported; as fibrinolysis is not suppressed adequately, it leads to a hemorrhagic diathesis (a tendency to hemorrhage).

PAI-1 is present in increased levels in various disease states (such as a number of forms of cancer), as well as in obesity and the metabolic syndrome. It has been linked to the increased occurrence of thrombosis in patients with these conditions.

In inflammatory conditions in which fibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression to fibrosis (pathological formation of connective tissue). Presumably, lower PAI levels would lead to less suppression of fibrinolysis and conversely a more rapid degradation of the fibrin.

Angiotensin II increases synthesis of plasminogen activator inhibitor-1, so it accelerates the development of atherosclerosis.

Pharmacology

Tiplaxtinin (PAI-039) is a small molecule inhibitor that is being studied for use in the attenuation of remodeling of blood vessels, a result of arterial hypertension and activation of the renin-angiotensin system.^[1]

Interactions

Plasminogen activator inhibitor-1 has been shown to interact with ORM1.^[2]

References

Further reading

External links

• The MEROPS online database for peptidases and their inhibitors: I04.020
• Plasminogen Activator Inhibitor 1 at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery 1a7c: HUMAN PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 IN COMPLEX WITH A PENTAPEPTIDE  1b3k: Plasminogen activator inhibitor-1  1c5g: PLASMINOGEN ACTIVATOR INHIBITOR-1  1db2: CRYSTAL STRUCTURE OF NATIVE PLASMINOGEN ACTIVATOR INHIBITOR-1  1dvm: ACTIVE FORM OF HUMAN PAI-1  1dvn: LATENT FORM OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)  1lj5: 1.8A Resolution Structure of Latent Plasminogen Activator Inhibitor-1(PAI-1)  1oc0: PLASMINOGEN ACTIVATOR INHIBITOR-1 COMPLEX WITH SOMATOMEDIN B DOMAIN OF VITRONECTIN  9pai: CLEAVED SUBSTRATE VARIANT OF PLASMINOGEN ACTIVATOR INHIBITOR-1