Plasminogen activator inhibitor-2
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| Location (UCSC) | Chr 18: 63.87 – 63.9 Mb | Chr 1: 107.44 – 107.46 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Plasminogen activator inhibitor-2 (placental PAI, SerpinB2, PAI-2), a
It is present only at detectable quantities in blood during pregnancy, as it is produced by the placenta, and may explain partially the increased rate of thrombosis during pregnancy. The majority of expressed PAI-2 remains unsecreted due to the presence of an inefficient internal signal peptide.
Interactions
PAI-2 has been reported to bind a series of intracellular and extracellular proteins. Whether PAI-2's physiological function is inhibition of the extracellular protease urokinase and/or whether PAI-2 has intracellular activities remains controversial. At least one of PAI-2's physiological functions may involve regulation of adaptive immunity.[5]
Structure and polymerization
Like other serpins, PAI-2 has three beta sheets (A, B, C) and nine alpha helices (hA-hI).[6][7] The structure of PAI-2 mutants have been solved, in which the 33-amino acid loop connecting helices C and D is deleted. This CD-loop is particularly flexible and difficult to stabilize, as the loop is known to translocate up to 54 Å during the formation of intramolecular disulfide bonds.[8] In addition to the CD-loop, notable motifs include the reactive center loop (RCL) spanning amino acids 379-383 and an N-terminal hydrophobic signal sequence.
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Despite their similar inhibitory targets, PAI-2 is phylogenetically distant from its counterpart plasminogen activator inhibitor-1 (PAI-1). As a member of the ovalbumin-related serpin family, PAI-2 is genetically similar to chicken ovalbumin (Gallus gallus), and is a close mammalian homolog.[9] Both ovalbumin and PAI-2 undergo secretion via uncleaved secretory signal peptides, although PAI-2 secretion is relatively much less efficient.[10]
PAI-2 exists in three polymeric states: monomeric, polymerigenic, and polymer (inactive state). Polymerization occurs by a so-called "loop-sheet" mechanism, in which the RCL of one molecule sequentially inserts into the A-beta-sheet of the next molecule. This process occurs preferentially when PAI-2 is in its polymerigenic form, which is stabilized by a disulfide bond between Cys-79 (located in the CD-loop) and Cys-161.[11] When PAI-2 is in its monomeric form, the CD-loop is vastly out-of-position for this disulfide linkage, and it must translocate a distance of 54 Å to become sufficiently close to Cys-161. Nevertheless, since the CD-loop is quite flexible, the monomeric and polymerigenic forms are fully interconvertible, and one state can be favored over the other by altering the redox environment of the protein.[8] Polymerization of PAI-2 occurs spontaneously under physiological conditions, for instance in the cytosol of placental cells.[12] Cytosolic PAI-2 tends to be monomeric, while PAI-2 in secretory organelles (which tend to be more oxidizing than the cytosol) is more prone to polymerization.[11] For these combined reasons, it is thought that PAI-2 may sense and respond to environmental redox potential.[8]
Mechanism
PAI-2 uses a suicide inhibition mechanism (a common mechanism for serpins) to irreversibly inactivate tissue plasminogen activator and urokinase.[6] First, the target serine protease docks to PAI-2 and catalyzes cleavage of the RCL, between residues Arg-380 and Thr-381. At this point, two outcomes are possible: the protease escapes, leaving an inactive PAI-2; or the protease forms a permanent, covalently-bonded complex with PAI-2, in which the protease is significantly distorted.
Biological Functions
Although extracellular (glycosylated) PAI-2 functions to regulate fibrinolysis, it remains unclear whether this inhibitory role is the main function of PAI-2. PAI-2 is predominantly intracellular. The secretory signal peptide of PAI-2 is relatively inefficient, perhaps by evolutionary design, as various mutations to the signal sequence can significantly enhance secretion efficiency.[10] PAI-2 is undetectable in adult plasma, and is typically only detectable during pregnancy, in myelomonocytic leukemias, or in gingival crevicular fluid; moreover, PAI-2 is a slower inhibitor than its counterpart PAI-1 by orders of magnitude (based on second order rate constants).[13] On the other hand, detailed intracellular roles for PAI-2 have not yet been conclusively established.
PAI-2 is upregulated during both pregnancy and immune responses. During pregnancy, PAI-2 is particularly present in the decidua and amniotic fluid, where it may protect membranes from digestion and aid in remodeling fetal and uterine tissues.[14] PAI-2 assists PAI-1 in regulating fibrinolysis and may help prevent overexpression of PAI-1, which increases risk of thrombosis.[14][15] Over the course of a pregnancy, PAI-2 plasma concentration rises from nearly-undetectable levels to 250 ng/mL (mostly in glycosylated form).[13]
Among immune cells, macrophages are the main producers of PAI-2, as both
Due to its position on chromosome 18 close to the bcl-2 protooncogene and several other serpins, PAI-2's role in apoptosis has been investigated, but current evidence remains inconclusive.[13][17] A recent study suggests PAI-2 may be a direct downstream target and activator of p53, and may directly stabilize p21; in addition, PAI-2 expression is increased in senescent fibroblasts and may arrest growth of young fibroplasts.[18]
Potential roles in cancer
The role of PAI-2 in cancer growth and metastasis is complex, as PAI-2 may have tumor-promoting and tumor-inhibiting effects. Notably, it is high expression of PAI-2 by tumor cells, not the host organism, which influences cancer growth.[19] Cancer cells may facilitate export of PAI-2 via microparticles.[19]
PAI-2 provides protection for cancer cells against plasmin-induced cell death, which can exert a lethal effect on tumors. This protection is particularly salient in brain metastases, which tend to express high levels of PAI-2 and
Although PAI-2 expression can promote metastasis to the brain, in other cases high PAI-2 expression significantly decreases metastasis to the lungs and other organs.[19][22] The particular effects of PAI-2 on metastasis may depend on cancer type and location in the body.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000197632 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062345 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 21395508.
- ^ PMID 16737556.
- PMID 16214170.
- ^ PMID 15561148.
- PMID 2494165.
- ^ PMID 14672654.
- ^ PMID 12682008.
- PMID 8626560.
- ^ PMID 7492756.
- ^ S2CID 39347062.
- PMID 1415704.
- ^ PMID 20130210.
- S2CID 260316614.
- PMID 28794016.
- ^ PMID 24644264.
- PMID 24581498.
- PMID 27048955.
- PMID 7816818.
Further reading
- Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (December 1992). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes". Electrophoresis. 13 (12): 960–9. S2CID 41855774.
- Ellis V, Wun TC, Behrendt N, Rønne E, Danø K (June 1990). "Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors". The Journal of Biological Chemistry. 265 (17): 9904–8. PMID 2161846.
- Estreicher A, Mühlhauser J, Carpentier JL, Orci L, Vassalli JD (August 1990). "The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes". The Journal of Cell Biology. 111 (2): 783–92. PMID 2166055.
- Samia JA, Alexander SJ, Horton KW, Auron PE, Byers MG, Shows TB, Webb AC (January 1990). "Chromosomal organization and localization of the human urokinase inhibitor gene: perfect structural conservation with ovalbumin". Genomics. 6 (1): 159–67. PMID 2303256.
- Schwartz BS, Monroe MC, Bradshaw JD (June 1989). "Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X". Blood. 73 (8): 2188–95. PMID 2471561.
- Ye RD, Ahern SM, Le Beau MM, Lebo RV, Sadler JE (April 1989). "Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin". The Journal of Biological Chemistry. 264 (10): 5495–502. PMID 2494165.
- Laug WE, Aebersold R, Jong A, Rideout W, Bergman BL, Baker J (June 1989). "Isolation of multiple types of plasminogen activator inhibitors from vascular smooth muscle cells". Thrombosis and Haemostasis. 61 (3): 517–21. S2CID 2349338.
- Kruithof EK, Cousin E (October 1988). "Plasminogen activator inhibitor 2. Isolation and characterization of the promoter region of the gene". Biochemical and Biophysical Research Communications. 156 (1): 383–8. PMID 2845977.
- Ye RD, Wun TC, Sadler JE (March 1987). "cDNA cloning and expression in Escherichia coli of a plasminogen activator inhibitor from human placenta". The Journal of Biological Chemistry. 262 (8): 3718–25. PMID 3029122.
- Antalis TM, Clark MA, Barnes T, Lehrbach PR, Devine PL, Schevzov G, Goss NH, Stephens RW, Tolstoshev P (February 1988). "Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor". Proceedings of the National Academy of Sciences of the United States of America. 85 (4): 985–9. PMID 3257578.
- Schleuning WD, Medcalf RL, Hession C, Rothenbühler R, Shaw A, Kruithof EK (December 1987). "Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells". Molecular and Cellular Biology. 7 (12): 4564–7. PMID 3325828.
- Webb AC, Collins KL, Snyder SE, Alexander SJ, Rosenwasser LJ, Eddy RL, Shows TB, Auron PE (July 1987). "Human monocyte Arg-Serpin cDNA. Sequence, chromosomal assignment, and homology to plasminogen activator-inhibitor". The Journal of Experimental Medicine. 166 (1): 77–94. PMID 3496414.
- Dickinson JL, Bates EJ, Ferrante A, Antalis TM (November 1995). "Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function". The Journal of Biological Chemistry. 270 (46): 27894–904. PMID 7499264.
- Mikus P, Urano T, Liljeström P, Ny T (December 1993). "Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms". European Journal of Biochemistry. 218 (3): 1071–82. PMID 7506655.
- Jensen PJ, Wu Q, Janowitz P, Ando Y, Schechter NM (March 1995). "Plasminogen activator inhibitor type 2: an intracellular keratinocyte differentiation product that is incorporated into the cornified envelope". Experimental Cell Research. 217 (1): 65–71. PMID 7867722.
- Akiyama H, Ikeda K, Kondo H, Kato M, McGeer PL (December 1993). "Microglia express the type 2 plasminogen activator inhibitor in the brain of control subjects and patients with Alzheimer's disease". Neuroscience Letters. 164 (1–2): 233–5. S2CID 40620114.
- Ragno P, Montuori N, Vassalli JD, Rossi G (June 1993). "Processing of complex between urokinase and its type-2 inhibitor on the cell surface. A possible regulatory mechanism of urokinase activity". FEBS Letters. 323 (3): 279–84. S2CID 1822666.
- Bartuski AJ, Kamachi Y, Schick C, Overhauser J, Silverman GA (August 1997). "Cytoplasmic antiproteinase 2 (PI8) and bomapin (PI10) map to the serpin cluster at 18q21.3". Genomics. 43 (3): 321–8. PMID 9268635.
- Mahony D, Stringer BW, Dickinson JL, Antalis TM (September 1998). "DNase I hypersensitive sites in the 5' flanking region of the human plasminogen activator inhibitor type 2 (PAI-2) gene are associated with basal and tumor necrosis factor-alpha-induced transcription in monocytes". European Journal of Biochemistry. 256 (3): 550–9. PMID 9780231.
- Nishida Y, Hayashi Y, Imai Y, Itoh H (February 1998). "Expression and localization of the urokinase-type plasminogen activator receptor (uPAR) in the human placenta". The Kobe Journal of Medical Sciences. 44 (1): 31–43. PMID 9846056.
External links
- The MEROPS online database for peptidases and their inhibitors: I04.007
- Plasminogen+Activator+Inhibitor+2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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![1jrr: HUMAN PLASMINOGEN ACTIVATOR INHIBITOR-2.[LOOP (66-98) DELETIONMUTANT] COMPLEXED WITH PEPTIDE MIMIckING THE REACTIVE CENTER LOOP](/File:PDB_1jrr_EBI.jpg)
![2arq: Human plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagdggvmtgr-oh](/File:PDB_2arq_EBI.png)
![2arr: Human plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagmggvmtgr-oh](/File:PDB_2arr_EBI.png)