MMP7

MMP7
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MMQ, 1MMR, 2MZE, 2DDY, 2Y6C, 2MZH, 1MMP, 2Y6D
Identifiers
Aliases	MMP7 , MMP-7, MPSL1, PUMP-1, matrix metallopeptidase 7
External IDs	OMIM: 178990 MGI: 103189 HomoloGene: 37619 GeneCards: MMP7
Gene location (Human) Chr. Chromosome 11 (human) [1] Band 11q22.2 Start 102,520,508 bp [1] End 102,530,750 bp [1]
Gene location (Mouse) Chr. Chromosome 9 (mouse) [2] Band 9 A1|9 2.46 cM Start 7,692,091 bp [2] End 7,699,586 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gallbladder islet of Langerhans pancreatic ductal cell caput epididymis body of pancreas minor salivary gland Achilles tendon lactiferous duct kidney endometrium Top expressed in crypt of lieberkuhn of small intestine Paneth cell duodenum jejunum jejunal mucosa gallbladder mucous gland cervix pancreas islet of Langerhans More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding zinc ion binding metal ion binding peptidase activity metalloendopeptidase activity hydrolase activity serine-type endopeptidase activity protein binding metallopeptidase activity Cellular component extracellular matrix extracellular region cell surface extracellular exosome extracellular space Biological process maternal process involved in female pregnancy estrous cycle human ageing extracellular matrix disassembly cellular response to mechanical stimulus response to nutrient levels collagen catabolic process proteolysis antibacterial peptide secretion extracellular matrix organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4316 17393 Ensembl ENSG00000137673 ENSMUSG00000018623 UniProt P09237 Q10738 Q3UN27 RefSeq (mRNA) NM_002423 NM_010810 NM_001319986 RefSeq (protein) NP_002414 NP_001306915 NP_034940 Location (UCSC) Chr 11: 102.52 – 102.53 Mb Chr 9: 7.69 – 7.7 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Matrilysin
Identifiers
EC no.	3.4.24.23
CAS no.	141256-52-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. ^[5] The enzyme (EC 3.4.24.23) has also been known as matrin, putative (or punctuated) metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). ^{[6] [7] [8] [9]} Human MMP-7 has a molecular weight around 30 kDa. ^[10]

Matrilysin was discovered by Sellers and Woessner in the uterus of the rat in 1988. ^[11] The complementary DNA (cDNA) of human MMP7 was isolated in 1988 by Muller et al. ^[12] MMP7 is a member of the matrix metalloproteinase (MMP) family consisting of structural-related zinc-dependent endopeptidases. The primary role of cleaved/activated MMP7 is to break down extracellular matrix by degrading macromolecules including casein, type I, II, IV, and V gelatins, fibronectin, and proteoglycan. ^{[12] [13]}

Gene, regulation, and expression

The human MMP7 is located on chromosome 11 q22.3. MMP genes are clustered in q region of human Chromosome 11 including matrilysin, collagenase-1, stromelysin1, stromelysin-2, and metalloelastase genes. It consists of 267 amino acids. The cDNA of MMP7 is 49% homologous to stromelysin-1. ^[12] Comparing to other members of MMP family, MMP7 does not have a C-terminal protein domain. ^[14]

The promoter of the human MMP7 contains a TATA box, an activator protein 1 (AP-1) site, and two inverted polyomavirus enhancer A-binding proteins 2 (PEA-3). The AP-1/PEA-3 binding motif is required and essential for MMP7 to be responsive to growth factors, oncogenes and phorbol ester. Also, the PEA and AP-1 are required for Matrilysin/CAT reporter constructs induced by tumor promoter 12-O-tetradecanoulphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In addition, the high level expression of AP-1 and its binding proteins were found to be associated with mutant Ki-Ras suggesting the high expression of matrilysin in Ras activated cells is AP-1 dependent. ^[12]

The expression of MMP7 is regulated by the Wnt/ β catenin signaling pathway, and mediated by transformation growth factor β (TGF-β).TGF-β stimulates ECM and suppresses the steady-state level of MMP7, stromelysin mRNAs, and secretion of zymogens. The isoforms of TGF-β inhibit MMP7 mRNA and protein in the human endometrium via progesterone mediated pathway. However, the opposite effects of TGF-β on MMP7 were observed among transformed cells. In human glioma cell lines and human squamous cell carcinoma cell line II-4, TGF-β stimulates the expression of MMP7 mRNA and proteins, and facilities the invasive behavior of cells. ^[15]

The promoter region of the human MMP7 gene contains two or more sites that are homologous to the NR-IL6 binding sequences indicating MMP7 can bind to IL-1 and IL-6. In addition, the level of MMP7 mRNA is elevated followed the treatment of tumor necrosis factor α (TNF- α) and IL-1 β in human mesangial cells. ^[12]

MMP7 are commonly expressed in epithelial cells including ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast. In addition, MMP7 is highly expressed in the luminal surface of dysplastic glands in human colorectal cancers. ^[13]

Structure

A MMP7 protein is bounded by four metal ions including a catalytic zinc ion, a structural zinc ion, and two calcium ions. The catalytic zinc ion binds to three His residues in the HEXGHXXGXXH region in tetracoordination. The calcium ion binding play important role in stabilizing the secondary structure. MMP7 has a shallow hydrophobic substrate-binding pocket. In contrast to MMP9 which has the longest hinge, MMP7 lacks hemopexin and does not have a hinge. Instead, MMP7 contains a variable C-terminal hemopexin-like domain facilitates substrate specificity. ^[15] The protein of MMP7 is secreted as zymogen. The prodoamin of MMP7 contains an approximately 9 kD highly conserved “cysteine switch” PRCGXPD sequence near the C-terminal containing cysteine residues. Cysteine residues bind to the catalytic zinc keeping the protein latent. The dissociation of cysteine –Zinc coordination starts from the cleavage of the first 30 amino acids of the prodomain, which leads to a conformation change, and further results in autoproteolysis and the cleavage of the whole prodomain at Glu-Tyr site. According to Woessner et al., the Mr of MMP7 is 28,000 for the latent form and 19,000 Mr for the active form after the cleavage of its prodomain. ^[12]

Interactions

Promatrilysin (Pro-MMP7) is converted from the latent form to the active form by endoproteinases, and plasmin. Plasmin cleaves at the site recognizable to trypsin, is considered as the most possible physiological activator. In vitro, plasmin can activate pro-MMP7 to 50% of its full activity. Also, researchers used activated recombinant pro-MMP7 and purified substrates to investigate the proteolytic activity of MMp7 in vitro, and found that MMP7 cleaves many protein substrates mainly including ECM components, proMMPs, and nonmatrix proteins. MMP7 cleaves the glycoprotein entactin that links laminin and collagen IV at about 100-600 times faster than collagenase-1. In addition, MMP7 can activate other MMPs. Activated MMP7 and APMA can increase the activity of collagenase-1, and MMP7 can also convert the latent progelatinase A to its active form. ^[12]

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, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The enzyme is involved in wound healing, and studies in mice suggest that it regulates the activity of defensins in intestinal mucosa. ^[16]

MMP7 was initially characterized by Woessner et al. It digests components of the extracellular matrix, cleaves the α 2 (I) chain of gelatin more rapidly, and digests the B chain of insulin at Ala¹⁴-Leu and Tyr¹⁶-Leu, and has no action on collagen types I, II, IV, V. The optimal pH of MMP7 is at 7 and the pI is at 5.9. MMP4 is inhibited by α 2-macroglobulin and TIMP. ^[11] The inhibition of MMP7 activity commonly relies on metal-chelating agents including EDTA and 1,10-phenanthroline, especially zinc chelation. Therefore, the selectivity of MMP7 inhibition is challenging since almost all members of MMPs family contain catalytic domains with zinc binding sites. TIMP-1 and 2 noncovalently bound to active MMP7 at the catalytic site inhibiting MMP7 activity. The activated MMP7 can also cleave the propeptides of proMMP2 and proMMP9 to facilitate tumor invasion. ^[17]

Normal tissue development

Quondamatteo et al. immunohistochemically stained MMP7, and localized MMP7 in early human liver development. They reported that MMP7 was presented in some hepatocytes and endothelial cells in the 6th gestational week, and only hematopoietic cells remained after that time. ^[18]

Tissue remodeling

In order for MMPs to escape TIMP inhibition, active MMP7s are recruited to the plasma membrane of epithelium inducing membrane-associated growth factors processing for epithelial repair and proliferation. In human endometrium, the expression of MMP7 mRNA increases at menstruation and remains high during the proliferative phase. Also, MMP-7 binds to the plasma membrane of epithelium containing cholesterol-rich domain. The bounded MMP7 is active and resistant to TIMP inhibition. It promotes the activity of the epithelial plasma membrane and associated substrates including E-cadherin, β4-integrin, TNF-alpha, RAS, heparin-binding EGF, IGF binding proteins and plasminogen. Further, this process promotes epithelial cell migration, proliferation and apoptosis. For menstruation, it promotes the endometrium regeneration after menstrual breakdown. ^[15] Huang et al. reported that the proteolytic activity of MMP7 plays major role in tissue remodeling in biliary atresia-associated liver fibrosis. ^[19]

Clinical significance

MMP7 cleaves collagen III/IV/V/IX/X/XI and proteoglycan indicating that MMP inhibitors can potentially be used in therapies that are involved in inhibition of tissue degradation, remodeling, anti-angiogenesis and inhibition of tumor invasion. ^{[13] [17]}

Role in Cancer

MMP7 is found to potentially be involved in tumor metastasis and inflammatory processes. ^[17] The upregulation of MMP7 is associated with many malignant tumors including esophagus, stomach, colon, liver, pancreas, and renal cell carcinomas. High MMP7 expression facilitates cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues. These degradations are associated with many mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, decubitus ulcer, and tumor metastasis/invasion. Activated MMP7 activates MMP2 and MMP9 zymogens, and mediates the proteolytic process of the precursors of tumor necrosis factors and urokinase plasminogen activators. ^[13]

Colon cancer and MMP7 expression

MMP7 cleaves cell surface proteins, promotes adhesion of cancer cells, and increases the potential of tumor metastasis. Higashi et al. reported that the binding of MMP7 to cholesterol sulfate on the cell surface plays a critical role in the cell membrane-related proteolytic action. Also, the internal Ile 29, Arg33, Arg51, and Trp 55 and 171-173 residues at MMP7 C-terminal located on the opposite side of the catalytic site of MMP7 are required for cholesterol sulfate binding. Wild type MMP7 can digest fibronectin, but mutant MMP7 fails to induce the aggregation of colon cancer cells. ^[20] In addition, Qasim et al. reported that MMP7 is highly expressed in advanced colorectal adenomatous polys with severe dysplasia. Further, MMP7 is involved in converting colorectal adenomas into malignant state and facilitating the growth. ^[21]

References

1. GRCh38: Ensembl release 89: ENSG00000137673 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018623 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Knox JD, Boreham DR, Walker JA, Morrison DP, Matrisian LM, Nagle RB, Bowden GT (Jan 1997). "Mapping of the metalloproteinase gene matrilysin (MMP7) to human chromosome 11q21→q22". Cytogenet Cell Genet. 72 (2–3): 179–82. doi:10.1159/000134181. PMID   8978768.
6. Muller D, Quantin B, Gesnel MC, Millon-Collard R, Abecassis J, Breathnach R (July 1988). "The collagenase gene family in humans consists of at least four members". The Biochemical Journal. 253 (1): 187–92. doi:10.1042/bj2530187. PMC   1149273 . PMID   2844164.
7. Woessner JF, Taplin CJ (November 1988). "Purification and properties of a small latent matrix metalloproteinase of the rat uterus". The Journal of Biological Chemistry. 263 (32): 16918–25. doi: 10.1016/S0021-9258(18)37479-9 . PMID   3182822.
8. Quantin B, Murphy G, Breathnach R (June 1989). "Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members". Biochemistry. 28 (13): 5327–34. doi:10.1021/bi00439a004. PMID   2550050.
9. Miyazaki K, Hattori Y, Umenishi F, Yasumitsu H, Umeda M (December 1990). "Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line". Cancer Research. 50 (24): 7758–64. PMID   2253219.
10. "MMP7 (human)". www.phosphosite.org. Retrieved 2021-10-05.
11. Woessner JF, Taplin CJ (November 1988). "Purification and properties of a small latent matrix metalloproteinase of the rat uterus". J. Biol. Chem. 263 (32): 16918–25. doi: 10.1016/S0021-9258(18)37479-9 . PMID   3182822.
12. Parks WC, Mecham RP (1988). "Matrix Metalloproteinases". 263. San Diego: Academic.{{cite journal}}: Cite journal requires |journal= (help)
13. Yokoyama Y, Grünebach F, Schmidt SM, Heine A, Häntschel M, Stevanovic S, Rammensee HG, Brossart P (2008). "Matrilysin (MMP-7) is a novel broadly expressed tumor antigen recognized by antigen-specific T cells". Clin. Cancer Res. 14 (17): 5503–11. doi:10.1158/1078-0432.CCR-07-4041. PMID   18765542. S2CID   8202181.
14. "Genes and Mapped Phenotypes". National Center for Biotechnology Information.{{cite journal}}: Cite journal requires |journal= (help)
15. Gaide Chevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P (2012). "Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration". Biochim. Biophys. Acta. 1824 (1): 146–56. doi:10.1016/j.bbapap.2011.09.003. PMID   21982799.
16. "Entrez Gene: MMP7 matrix metallopeptidase 7 (matrilysin, uterine)".
17. Edman K, Furber M, Hemsley P, Johansson C, Pairaudeau G, Petersen J, Stocks M, Tervo A, Ward A, Wells E, Wissler L (2011). "The discovery of MMP7 inhibitors exploiting a novel selectivity trigger". ChemMedChem. 6 (5): 769–73. doi:10.1002/cmdc.201000550. PMID   21520417. S2CID   32715622.
18. Quondamatteo F, Knittel T, Mehde M, Ramadori G, Herken R (1999). "Matrix metalloproteinases in early human liver development". Histochem. Cell Biol. 112 (4): 277–82. doi:10.1007/s004180050448. PMID   10550612. S2CID   711819.
19. Huang CC, Chuang JH, Chou MH, Wu CL, Chen CM, Wang CC, Chen YS, Chen CL, Tai MH (2005). "Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis". Mod. Pathol. 18 (7): 941–50. doi: 10.1038/modpathol.3800374 . PMID   15696117.
20. Higashi S, Oeda M, Yamamoto K, Miyazaki K (2008). "Identification of amino acid residues of matrix metalloproteinase-7 essential for binding to cholesterol sulfate". J. Biol. Chem. 283 (51): 35735–44. doi: 10.1074/jbc.M806285200 . PMID   18955490.
21. Qasim BJ, Ali HH, Hussein AG (2013). "Immunohistochemical expression of matrix metalloproteinase-7 in human colorectal adenomas using specified automated cellular image analysis system: a clinicopathological study". Saudi J Gastroenterol. 19 (1): 23–7. doi: 10.4103/1319-3767.105916 . PMC   3603485 . PMID   23319034.

Further reading

• Massova I, Kotra LP, Fridman R, Mobashery S (1998). "Matrix metalloproteinases: structures, evolution, and diversification". FASEB J. 12 (25n26): 1075–95. CiteSeerX   10.1.1.31.3959 . doi:10.1142/S0217984998001256. PMID   9737711.
• Nagase H, Woessner JF (1999). "Matrix metalloproteinases". J. Biol. Chem. 274 (31): 21491–4. doi: 10.1074/jbc.274.31.21491 . PMID   10419448.

External links

• Matrilysin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• The MEROPS online database for peptidases and their inhibitors: M10.008 ^{[ permanent dead link ]}