MMP9

Matrix metallopeptidase 9

PDB rendering based on 1itv.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MMP9 ; CLG4B; GELB; MANDP2; MMP-9
External IDs OMIM: 120361 MGI: 97011 HomoloGene: 3659 ChEMBL: 321 GeneCards: MMP9 Gene
EC number 3.4.24.35
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 4318 17395
Ensembl ENSG00000100985 ENSMUSG00000017737
UniProt P14780 P41245
RefSeq (mRNA) NM_004994 NM_013599
RefSeq (protein) NP_004985 NP_038627
Location (UCSC) Chr 20:
46.01 – 46.02 Mb		 Chr 2:
164.94 – 164.96 Mb
PubMed search

Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene [1] encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.[2]

Function

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, learning and memory, as well as in pathological processes, such as arthritis, intracerebral hemorrhage,[3] and metastasis.[4] Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens and other extracellular matrix proteins.[5] Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling.[1]

Thrombospondins, intervertebral disc proteins, regulate interaction with matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling.[6]

Neutrophil action

MMP9, along with elastase, appears to be a regulatory factor in neutrophil migration across the basement membrane.[7]

MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of IL-1β, and cleavage of several chemokines.[8] In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in sepsis.[9]

Angiogenesis

MMP9 may play an important role in angiogenesis and neovascularization. For example, MMP9 appears to be involved in the remodeling associated with malignant glioma neovascularization.[10] It is also a key regulator of growth plate formation- both growth plate angiogenesis and the generation of hypertrophic chondrocytes. Knock-out models of MMP9 result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes.[11] Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis [12]

Wound repair

MMP9 is greatly upregulated during human respiratory epithelial healing.[13] Using a MMP9 deficient mouse model, it was seen that MMP9 coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing.[14] When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.[15]

Structure

ProMMP9 (pro-peptide (red), catalytic domain (green) with fibronectin domains (cyan), with detail of the "cysteine switch" (from PDB entry 1L6J)

MMP9 is synthesized as preproenzyme of 707 amino-acid residues, including a 19 amino acid signal peptide and secreted as an inactive pro-MMP. The human MMP9 proenzyme consists of five domains. The amino-terminal propeptide, the zinc-binding catalytic domain and the carboxyl-terminal hemopexin-like domain are conserved. Its primary structure comprises several domain motifs. The propeptide domain is characterized by a conserved PRCGVPD sequence. The Cys within this sequence is known as the “cysteine switch”. It ligates the catalytic zinc to maintain the enzyme in an inactive state.[2]

MMP-9 catalytic domain in complex with a fluorogenic synthetic peptidic substrate. From PDB entry 4JIJ.[16]

Activation is achieved through an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin generates active MMP-3 from its zymogen. Active MMP-3 cleaves the propeptide from the 92-kDa pro-MMP-9, yielding an 82-kDa enzymatically active enzyme.[17] In the active enzyme a substrate, or a fluorogenic activity probe.,[16] replaces the propetide in the enzyme active site where it is cleaved. The catalytic domain contains two zinc and three calcium atoms. The catalytic zinc is coordinated by three histidines from the conserved HEXXHXXGXXH binding motif. The other zinc atom and the three calcium atoms are structural. A conserved methionine, which forms a unique “Met-turn” structure categorizes MMP9 as a metzincin.[18] Three type II fibronectin repeats are inserted in the catalytic domain, although these domains are omitted in most crystallographic structures of MMP9 in complex with inhibitors.The active form of MMP9 also contains a C-terminal hemopexin-like domain. This domain is ellipsoidal in shape, formed by four β-propeller blades and an α-helix. Each blade consists of four antiparallel β-strands arranged around a funnel-like tunnel that contains two calcium and two chloride ions.[19] The hemopexin domain is important to facilitate the cleavage of triple helical interstitial collagens. .

Clinical significance

MMP9 has been found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

Arthritis

Elevated MMP9 levels can be found in the cases of rheumatoid arthritis[20] and focal brain ischemia.[21]

Cancer

One of MMP9's most widely-associated pathologies is the relationship to cancer, due to its role in extracellular matrix remodeling and angiogenesis. For example, its increased expression was seen in a metastatic mammary cancer cell line.[22] Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis.[23] However, because of its physiologic function, it may be difficult to leverage Gelatinase B inhibition into cancer therapy modalities. However, Gelatinase B has been investigated in tumor metastasis diagnosis- Complexes of Gelatinase B/Tissue Inhibitors of Metalloproteinases are seen to be increased in gastrointestinal cancer and gynecologic malignancies [24]

MMPs such as MMP9 can be involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis.[25]

Cardiovascular

MMP9 levels increase with the progression of idiopathic atrial fibrillation.[26]

MMP9 has been found to be associated with the development of aortic aneurysms,[27] and its disruption prevents the development of aortic aneurysms.[28] Doxycycline suppresses the growth of aortic aneurysms through its inhibition of MMP9.[29]

References

  1. 1 2 "Matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)".
  2. 1 2 Nagase H, Woessner JF (1999). "Matrix metalloproteinases". The Journal of Biological Chemistry 274 (31): 21491–4. doi:10.1074/jbc.274.31.21491. PMID 10419448.
  3. ↑ Wang J, Tsirka SE (2005). "Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage.". Brain 128 (7): 1622–33. doi:10.1093/brain/awh489. PMID 15800021.
  4. ↑ Van; Vandooren, J; den Steen, PE; Opdenakker, G. (2013). "Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9) The next decade". Crit Rev Biochem Mol Biol. 48 (3): 222–72. doi:10.3109/10409238.2013.770819. PMID 23547785.
  5. ↑ Van; den Steen, PE; Dubois, B; Nelissen, I; Rudd, PM; Dwek, RA; Opdenakker, G (2002). "Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9)".". Crit Rev Biochem Mol Biol 37 (6): 375–536. doi:10.1080/10409230290771546. PMID 12540195.
  6. ↑ Hirose Y, Chiba K, Karasugi T, Nakajima M, Kawaguchi Y, Mikami Y, Furuichi T, Mio F, Miyake A, Miyamoto T, Ozaki K, Takahashi A, Mizuta H, Kubo T, Kimura T, Tanaka T, Toyama Y, Ikegawa S (May 2008). "A Functional Polymorphism in THBS2 that Affects Alternative Splicing and MMP Binding Is Associated with Lumbar-Disc Herniation". Am. J. Hum. Genet. 82 (5): 1122–9. doi:10.1016/j.ajhg.2008.03.013. PMC 2427305. PMID 18455130.
  7. ↑ Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A (1996). "Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane". Am. J. Respir. Cell Mol. Biol. 14 (3): 288–95. doi:10.1165/ajrcmb.14.3.8845180. PMID 8845180.
  8. ↑ Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, Proost P, Van Damme J (2001). "MMP9 functions as regulator and effector in leukocyte biology". Journal of Leukocyte Biology 69 (6): 851–9. PMID 11404367.
  9. ↑ Dubois B, Starckx S, Pagenstecher A, Oord Jv, Arnold B, Opdenakker G (2002). "MMP9 deficiency protects against endotoxin shock". Eur. J. Immunol. 32 (8): 2163–71. doi:10.1002/1521-4141(200208)32:8<2163::AID-IMMU2163>3.0.CO;2-Q. PMID 12209628.
  10. ↑ Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR (1999). "Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas". British Journal of Cancer 79 (11-12): 1828–35. doi:10.1038/sj.bjc.6690291. PMC 2362801. PMID 10206300.
  11. ↑ Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z (1998). "MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes". Cell 93 (3): 411–22. doi:10.1016/s0092-8674(00)81169-1. PMC 2839071. PMID 9590175.
  12. ↑ Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S (2002). "Recruitment of Stem and Progenitor Cells from the Bone Marrow Niche Requires MMP-9 Mediated Release of Kit-Ligand". Cell 109 (5): 625–37. doi:10.1016/s0092-8674(02)00754-7. PMC 2826110. PMID 12062105.
  13. ↑ Buisson AC, Zahm JM, Polette M, Pierrot D, Bellon G, Puchelle E, Birembaut P, Tournier JM (1996). "MMP9 is involved in the in vitro wound repair of human respiratory epithelium". Journal of Cellular Physiology 166 (2): 413–26. doi:10.1002/(sici)1097-4652(199602)166:2<413::aid-jcp20>3.0.co;2-a. PMID 8592002.
  14. ↑ Mohan R, Chintala SK, Jung JC, Villar WV, McCabe F, Russo LA, Lee Y, McCarthy BE, Wollenberg KR, Jester JV, Wang M, Welgus HG, Shipley JM, Senior RM, Fini ME (2001). "Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration". The Journal of Biological Chemistry 277 (3): 2065–72. doi:10.1074/jbc.m107611200. PMID 11689563.
  15. ↑ Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, Wen FQ, Abe S, Wang X, Atkinson JJ, Shipley JM, Senior RM, Rennard SI (2014). "Matrix metalloproteinase-9 activates TGF-ss and stimulates fibroblast contraction of collagen gels". American Journal of Physiology. Lung Cellular and Molecular Physiology 306 (11): L1006–15. doi:10.1152/ajplung.00015.2014. PMID 24705725.
  16. 1 2 Tranchant I, Vera L, Czarny B, Amoura M, Cassar E, Beau F, Stura EA, Dive V (2014). "Halogen bonding controls selectivity of FRET substrate probes for MMP-9". chemistry & Biology 21 (3): 408–413. doi:10.1016/j.chembiol.2014.01.008. PMID 24583051.
  17. ↑ Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP (1999). "Activation of Matrix Metalloproteinase-9 (MMP-9) via a Converging Plasmin/Stromelysin-1 Cascade Enhances Tumor Cell Invasion". The Journal of Biological Chemistry 274 (19): 13066–13076. doi:10.1074/jbc.274.19.13066. PMID 10224058.
  18. ↑ Bode W, Gomis-Rüth FX, Stöckler W (1993). "Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'". FEBS Lett. 331 (1-2): 134–140. doi:10.1016/0014-5793(93)80312-I. PMID 8405391.
  19. ↑ Gomis-Rüth FX, Gohlke U, Betz M, Knäuper V, Murphy G, López-Otín C, Bode W (1996). "The helping hand of collagenase-3 (MMP-13): 2.7 A crystal structure of its C-terminal haemopexin-like domain.". J. Mol. Biol. 264 (3): 556–566. doi:10.1006/jmbi.1996.0661. PMID 8969305.
  20. ↑ Gruber BL, Sorbi D, French DL, Marchese MJ, Nuovo GJ, Kew RR, Arbeit LA (1996). "Markedly Elevated Serum MMP-9 (Gelatinase B) Levels in Rheumatoid Arthritis: A Potentially Useful Laboratory Marker". Clinical Immunology and Immunopathology 78 (2): 161–71. doi:10.1006/clin.1996.0025. PMID 8625558.
  21. ↑ Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR (1997). "Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia". Neuroscience Letters 238 (1-2): 53–6. doi:10.1016/s0304-3940(97)00859-8. PMID 9464653.
  22. ↑ Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, Noonan DM, Natali PG, Albini A (2000). "The α3β1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (mmp-9) activity". International Journal of Cancer 87 (3): 336–42. doi:10.1002/1097-0215(20000801)87:3<336::aid-ijc5>3.3.co;2-v. PMID 10897037.
  23. ↑ Farina AR, Mackay AR (2014). "Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression". Cancers (Basel) 6 (1): 240–96. doi:10.3390/cancers6010240. PMC 3980597. PMID 24473089.
  24. ↑ Zucker S, Lysik RM, DiMassimo BI, Zarrabi HM, Moll UM, Grimson R, Tickle SP, Docherty AJ (1995). "Plasma assay of gelatinase B: tissue inhibitor of metalloproteinase complexes in cancer". Cancer 76 (4): 700–708. doi:10.1002/1097-0142(19950815)76:4<700::aid-cncr2820760426>3.0.co;2-5. PMID 8625169.
  25. ↑ Groblewska M, Siewko M, Mroczko B, Szmitkowski M (2012). "The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer". Folia Histochem. Cytobiol. 50 (1): 12–9. doi:10.2478/18691. PMID 22532131.
  26. ↑ Li M, Yang G, Xie B, Babu K, Huang C (2014). "Changes in matrix metalloproteinase-9 levels during progression of atrial fibrillation". J. Int. Med. Res. 42 (1): 224–30. doi:10.1177/0300060513488514. PMID 24345823.
  27. ↑ Newman KM, Ogata Y, Malon AM, Irizarry E, Gandhi RH, Nagase H, Tilson MD (1994). "Identification of matrix metalloproteinases 3 (stromelysin-1) and 9 (gelatinase B) in abdominal aortic aneurysm.". Arteriosclerosis and thrombosis: a journal of vascular biology 14 (8): 1315–20. doi:10.1161/01.atv.14.8.1315. PMID 8049193.
  28. ↑ Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW (2000). "Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms". The Journal of Clinical Investigation 105 (11): 1641–9. doi:10.1172/jci8931. PMC 300851. PMID 10841523.
  29. ↑ Lindeman JH, Abdul-Hussien H, van Bockel JH, Wolterbeek R, Kleemann R (April 2009). "Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells". Circulation 119 (16): 2209–16. doi:10.1161/CIRCULATIONAHA.108.806505. PMID 19364980.

Further reading

External links

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