| Description | MMP-9 is a Zn+2 dependent endopeptidase, synthesized and secreted in monomeric form as zymogen. The structure is almost similar to MMP2, another member of matrixmetalloproteinase family. The nascent form of the protein shows an N-terminal signal sequence ("pre" domain) that directs the protein to the endoplasmic reticulum. The pre domain is followed by a propeptide-"pro" domain that maintains enzyme-latency until cleaved or disrupted, and a catalytic domain that contains the conserved zinc-binding region. A hemopexin/vitronectin-like domain is also seen, that is connected to the catalytic domain by a hinge or linker region. The hemopexin domain is involved in TIMP (Tissue Inhibitors of Metallo-Proteinases) binding e.g. TIMP-1 & TIMP-3, the binding of certain substrates, membrane activation, and some proteolytic activities. It also shows a series of three head-to-tail cysteine-rich repeats within its catalytic domain. These inserts resemble the collagen-binding type II repeats of fibronectin and are required to bind and cleave collagen and elastin.
Like other proteolytic enzymes, MMP-9 is first synthesized as inactive proenzyme or zymogens. Activation of proMMP-9 is mediated by plasminogen activator/plasmin (PA/plasmin) system. The regulation of MMP-9 activity is also controlled through TIMP-3. |
| Expression | MMP-9 expression is regulated by several cytokines and growth factors, including interleukins, interferons, EGF (Epidermal growth factor), NGF (Nerve growth factor), basic FGF (Fibroblast growth factor), VEGF (Vascular endothelial growth factor), PDGF (Platelet derived growth), TNF-a (Tumor necrosis factor), TGF-b (Tranforming growth factor), the extracellular matrix metalloproteinase inducer EMMPRIN and also osteopontin. Many of these stimuli induce the expression and/or activation of c-fos and c-jun proto-oncogene products, which heterodimerize and bind activator protein-1 (AP-1) sites within of MMP9 gene promoters. |
| Localisation | Peri/extracellular |
| Function | Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests decorin, elastin, fibrillin, laminin, gelatin (denatured collagen), and types IV, V, XI and XVI collagen and also activates growth factors like proTGFb and proTNFa. Physiologically, MMP-9 in coordination with other MMPs, play a role in normal tissue remodeling events such as neurite gowth, embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP-9 with other MMPs is also involved in osteoblastic bone formation and/or inhibits osteoclastic bone resorption. |
| Homology | Homology in amino acid sequence is seen with the other members of Metalloproteinase family especially with MMP-2. |
| Entity | Invasive and highly tumorigenic cancers |
| Disease | Elevated expression of MMP-9, along with MMP-2 is usually seen in invasive and highly tumorigenic cancers such as colorectal tumors, gastric carcinoma, pancreatic carcinoma, breast cancer, oral cancer, melanoma, malignant gliomas, chondrosarcoma, gastrointestinal adenocarcinoma. Levels are also increased in malignant astrocytomas, carcinomatous meningitis, and brain metastases. |
| Oncogenesis | MMPs promote tumor progression and metastasis in invasive cancers by degradation of the ECM (ExtraCellular Matrix), which consists of two main components: Basement membranes and interstitial connective tissue. Though ECM comprises of many proteins (laminin-5, proteoglycans, entactin, osteonectin) collagen IV is the major element. MMP-2 & MMP-9 efficiently degrade collagen IV and laminin-5 thereby, assisting the metastatic cancerous cells to pass through the basement membrane. The degradation of ECM not only assists migration of metastatic cancerous cells, but also allows enhanced tumor growth by providing necessary space. Further, it is noteworthy that the ratio of active to latent form of MMP-9 increased with tumor progression in invasive cancers. MMP-9, with its family members also promotes angiogenesis (a critical process required for tumor cell survival) by degrading the vascular basement membrane interstitium and also by releasing sequestered VEGF, which is a well know angiogenic molecule. Localization of MMP9 to the cell surface is required to promote tumor invasion and angiogenesis. |
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| Entity | Arthritis, autosomal recessive osteolysis disorder, coronary artery disease, pulmonary-emphysema and diabetic retinopathy. |
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| Nomenclature | | HGNC | MMP9 7176 |
| Entrez_Gene | MMP9 4318 matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) |
| Cards |
|---|
| Atlas | MMP9ID41408ch20q11 |
| GeneCards | MMP9 |
| Ensembl | MMP9 [Search_View] ENSG00000100985 [Gene_View] |
| Genatlas | MMP9 |
| GeneLynx | MMP9 |
| eGenome | MMP9 |
| euGene | 4318 |
| Genomic and cartography |
|---|
| GoldenPath | MMP9 - chr20:44070954-44078607 + 20q12-q13 [Description] (hg18-Mar_2006) |
| Ensembl | MMP9 - 20q12-q13 [CytoView] |
| NCBI | Mapview |
| OMIM | Disease map [OMIM] |
| HomoloGene | MMP9 |
| Gene and transcription | | Genbank | AK313137 [ ENTREZ ] |
| Genbank | AW468235 [ ENTREZ ] |
| Genbank | BC006093 [ ENTREZ ] |
| Genbank | CN288579 [ ENTREZ ] |
| Genbank | DQ896791 [ ENTREZ ] |
| RefSeq | NM_004994 [ SRS ] NM_004994 [ ENTREZ ] |
| RefSeq | AC_000063 [ SRS ] AC_000063 [ ENTREZ ] |
| RefSeq | AC_000152 [ SRS ] AC_000152 [ ENTREZ ] |
| RefSeq | NC_000020 [ SRS ] NC_000020 [ ENTREZ ] |
| RefSeq | NT_011362 [ SRS ] NT_011362 [ ENTREZ ] |
| RefSeq | NW_001838666 [ SRS ] NW_001838666 [ ENTREZ ] |
| RefSeq | NW_927339 [ SRS ] NW_927339 [ ENTREZ ] |
| AceView | MMP9 AceView - NCBI |
| Unigene | Hs.297413 [ SRS ] Hs.297413 [ NCBI ]
HS297413 [ spliceNest ] |
| Fast-db | 12552 (alternative variants) |
| Protein : pattern, domain, 3D structure |
|---|
| SwissProt | P14780 [ SRS] P14780 [ EXPASY ] P14780 [ INTERPRO ] P14780 [ UNIPROT ] |
| Prosite | PS00546 CYSTEINE_SWITCH [ SRS ] PS00546 CYSTEINE_SWITCH [ Expasy ] |
| Prosite | PS00023 FN2_1 [ SRS ] PS00023 FN2_1 [ Expasy ] |
| Prosite | PS51092 FN2_2 [ SRS ] PS51092 FN2_2 [ Expasy ] |
| Prosite | PS00024 HEMOPEXIN [ SRS ] PS00024 HEMOPEXIN [ Expasy ] |
| Prosite | PS00142 ZINC_PROTEASE [ SRS ] PS00142 ZINC_PROTEASE [ Expasy ] |
| Interpro | IPR000562 FN_type2_col_bd [ SRS ] IPR000562 FN_type2_col_bd [ EBI ] |
| Interpro | IPR000585 Hemopexin [ SRS ] IPR000585 Hemopexin [ EBI ] |
| Interpro | IPR001818 Pept_M10A_M12B [ SRS ] IPR001818 Pept_M10A_M12B [ EBI ] |
| Interpro | IPR006025 Pept_M_Zn_BS [ SRS ] IPR006025 Pept_M_Zn_BS [ EBI ] |
| Interpro | IPR006026 Peptidase_M [ SRS ] IPR006026 Peptidase_M [ EBI ] |
| Interpro | IPR002477 Peptidoglycan-bd-like [ SRS ] IPR002477 Peptidoglycan-bd-like [ EBI ] |
| Interpro | IPR006970 PT [ SRS ] IPR006970 PT [ EBI ] |
| CluSTr | P14780 |
| Pfam | PF00040 fn2 [ SRS ] PF00040 fn2 [ Sanger ] pfam00040 [ NCBI-CDD ] |
| Pfam | PF00045 Hemopexin [ SRS ] PF00045 Hemopexin [ Sanger ] pfam00045 [ NCBI-CDD ] |
| Pfam | PF00413 Peptidase_M10 [ SRS ] PF00413 Peptidase_M10 [ Sanger ] pfam00413 [ NCBI-CDD ] |
| Pfam | PF01471 PG_binding_1 [ SRS ] PF01471 PG_binding_1 [ Sanger ] pfam01471 [ NCBI-CDD ] |
| Pfam | PF04886 PT [ SRS ] PF04886 PT [ Sanger ] pfam04886 [ NCBI-CDD ] |
| Smart | SM00059 FN2 [EMBL] |
| Smart | SM00120 HX [EMBL] |
| Smart | SM00235 ZnMc [EMBL] |
| Prodom | PD000995 FN_Type_II[INRA-Toulouse] |
| Prodom | P14780 MMP9_HUMAN [ Domain structure ] P14780 MMP9_HUMAN [ sequences sharing at least 1 domain ] |
| Blocks | P14780 |
| PDB | 1GKC [ SRS ] 1GKC [ PdbSum ], 1GKC [ IMB ] 1GKC [ RSDB ] |
| PDB | 1GKD [ SRS ] 1GKD [ PdbSum ], 1GKD [ IMB ] 1GKD [ RSDB ] |
| PDB | 1ITV [ SRS ] 1ITV [ PdbSum ], 1ITV [ IMB ] 1ITV [ RSDB ] |
| PDB | 1L6J [ SRS ] 1L6J [ PdbSum ], 1L6J [ IMB ] 1L6J [ RSDB ] |
| PDB | 1LKG [ SRS ] 1LKG [ PdbSum ], 1LKG [ IMB ] 1LKG [ RSDB ] |
| PDB | 2OVX [ SRS ] 2OVX [ PdbSum ], 2OVX [ IMB ] 2OVX [ RSDB ] |
| PDB | 2OVZ [ SRS ] 2OVZ [ PdbSum ], 2OVZ [ IMB ] 2OVZ [ RSDB ] |
| PDB | 2OW0 [ SRS ] 2OW0 [ PdbSum ], 2OW0 [ IMB ] 2OW0 [ RSDB ] |
| PDB | 2OW1 [ SRS ] 2OW1 [ PdbSum ], 2OW1 [ IMB ] 2OW1 [ RSDB ] |
| PDB | 2OW2 [ SRS ] 2OW2 [ PdbSum ], 2OW2 [ IMB ] 2OW2 [ RSDB ] |
| HPRD | 00387 |
| Protein Interaction databases |
|---|
| DIP | P14780 |
| IntAct | P14780 |
| Polymorphism : SNP, mutations, diseases |
|---|
| OMIM | 120361;603932 [ map ] |
| GENECLINICS | 120361;603932 |
| SNP | MMP9 [dbSNP-NCBI] |
| SNP | NM_004994 [SNP-NCI] |
| SNP | MMP9 [GeneSNPs - Utah] MMP9] [HGBASE - SRS] |
| HAPMAP | MMP9 [HAPMAP] |
| COSMIC | MMP9 [Somatic mutation (COSMIC-CGP-Sanger)] |
| HGMD | MMP9 |
| General knowledge |
|---|
| Family Browser | MMP9 [UCSC Family Browser] |
| SOURCE | NM_004994 |
| SMD | Hs.297413 |
| SAGE | Hs.297413 |
| Enzyme | 3.4.24.35 [ Enzyme-Expasy ] 3.4.24.35 [ Enzyme-SRS ] 3.4.24.35 [ IntEnz-EBI ] 3.4.24.35 [ BRENDA ] 3.4.24.35 [ KEGG ] 3.4.24.35 [ WIT ] |
| GO | skeletal development [Amigo] skeletal development |
| GO | gelatinase B activity [Amigo] gelatinase B activity |
| GO | calcium ion binding [Amigo] calcium ion binding |
| GO | collagen binding [Amigo] collagen binding |
| GO | extracellular region [Amigo] extracellular region |
| GO | proteinaceous extracellular matrix [Amigo] proteinaceous extracellular matrix |
| GO | extracellular space [Amigo] extracellular space |
| GO | proteolysis [Amigo] proteolysis |
| GO | collagenase activity [Amigo] collagenase activity |
| GO | metabolic process [Amigo] metabolic process |
| GO | zinc ion binding [Amigo] zinc ion binding |
| GO | extracellular matrix organization and biogenesis [Amigo] extracellular matrix organization and biogenesis |
| GO | macrophage differentiation [Amigo] macrophage differentiation |
| GO | collagen catabolic process [Amigo] collagen catabolic process |
| GO | positive regulation of apoptosis [Amigo] positive regulation of apoptosis |
| BIOCARTA | Inhibition of Matrix Metalloproteinases [Genes] |
| KEGG | Leukocyte transendothelial migration |
| PubGene | MMP9 |
| TreeFam | MMP9 |
| CTD | 4318 [Comparative ToxicoGenomics Database] |
| Other databases |
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| Probes |
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| Probe | MMP9 Related clones (RZPD - Berlin) |
| PubMed |
|---|
| PubMed | 499 Pubmed reference(s) in LocusLink |
| An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides. |
| Hangauer DG, Monzingo AF, Matthews BW |
| Biochemistry. 1984 ; 23 (24) : 5730-5741. |
| PMID 6525336 |
| |
| Activity of type IV collagenases in benign and malignant breast disease. |
| Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR |
| British journal of cancer. 1993 ; 67 (5) : 1126-1131. |
| PMID 8494711 |
| |
| Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. |
| Stetler-Stevenson WG |
| The Journal of clinical investigation. 1999 ; 103 (9) : 1237-1241. |
| PMID 10225966 |
| |
| Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. |
| Zeng ZS, Cohen AM, Guillem JG |
| Carcinogenesis. 1999 ; 20 (5) : 749-755. |
| PMID 10334190 |
| |
| Matrix Metalloproteinases and TIMPs. |
| Woessner JF, Nagase H |
| New York. : page Ox. |
| |
| Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. |
| Yu Q, Stamenkovic I |
| Genes & development. 2000 ; 14 (2) : 163-176. |
| PMID 10652271 |
| |
| The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. |
| John A, Tuszynski G |
| Pathology oncology research : POR. 2001 ; 7 (1) : 14-23. |
| PMID 11349215 |
| |
| How matrix metalloproteinases regulate cell behavior. |
| Sternlicht MD, Werb Z |
| Annual review of cell and developmental biology. 2001 ; 17 : 463-516. |
| PMID 11687497 |
| |
| Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials. |
| Bloomston M, Zervos EE, Rosemurgy AS 2nd |
| Annals of surgical oncology. 2002 ; 9 (7) : 668-674. |
| PMID 12167581 |
| |
| Matrix metalloproteinases as novel disease markers in Takayasu arteritis. |
| Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, Nakamura T, Yamashita S, Matsuzawa Y |
| Circulation. 2003 ; 108 (12) : 1469-1473. |
| PMID 12952836 |
| |
| Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation. |
| Rangaswami H, Bulbule A, Kundu GC |
| The Journal of biological chemistry. 2004 ; 279 (37) : 38921-38935. |
| PMID 15247285 |
| |
| JNK1 differentially regulates osteopontin-induced nuclear factor-inducing kinase/MEKK1-dependent activating protein-1-mediated promatrix metalloproteinase-9 activation. |
| Rangaswami H, Bulbule A, Kundu GC |
| The Journal of biological chemistry. 2005 ; 280 (19) : 19381-19392. |
| PMID 15757900 |
| |
