Activation of Matrix Metalloproteinases (Homo sapiens)

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3, 5, 10, 1823, 28, 3623, 28, 3616, 3442, 4416, 342, 6, 9, 22, 27...1319, 20, 3115, 19, 3241813, 4137, 384, 123311, 211, 14, 24, 2562617264116, 3930, 357, 408cytosolGolgi lumenMMP25(22-?) MMP9(60-707)CTSL2 SPOCK3MMP1 (2, 3, 7, 10,13)CMA1 CTRB1(34-164) MMP13(55-471) MMP1(100-469) MMP2,3,7,10,11MMP16 MMP10 MMP1(20-469)CTRB1(19-31) PRSS2(24-247) COL18A1(1572-11754)MMP2(67-109)TPSAB1 MMP13(55-103) MMP2(110-660)MMP2(30-660)MMP7(51-267)MMP1(84-469)MMP24(156-?) PRSS1(24-247) MMP14:TIMP2:MMP2intermediate formMT-MMPsPLG(581-810) MMP9(20-59)MMP7(51-94)TIMP2 PRSS1(24-247) PRSS1(24-247) PLG(581-810) TIMP1MMP9(20-106)MMP14 PLG(20-580) MMP25 MMP2(110-660) TIMP2 MMP1(20-53)proMMP9 activatingproteasesMT-MMPsMMP17(36-?) MMP10 MMP14 MMP14:TIMP:MMP2CTSK MMP14 Highly sulphatedglycosaminoglycansMMP14 MMP1(54-469)MMP9(107-707)PRSS1(24-247) PLG(20-580) MMP3(18-54)MMP24(156-?) MMP13 MMP7(18-267)MMP17(126-?) MMP10MMP14 MMP13(77-471)MMP1(100-469) MMP2(67-660) proMMP9:TIMP1proMMP10 activatorsHeparins ELANE MMP11 CTRB1(167-263) MMP17(126-?) MMP13 intermediateform fragmentsMMP3(18-477)MMP16 MMP13(20-471)MMP2(67-660)MMP13(20-57)MMP7(95-267)MMP2(30-660) MMP9(20-707)FURINCTRB1(19-31) PLG(581-810) CTRB1(167-263) MMP16(32-607) MMP3, CTSK, CTSL2CTRB1(34-164) MMP13(58-103) MMP14 PRSS1(24-247) proMMP3 initialactivatorsMMP9(20-707) MMP8CTSG PLG(20-580) PLG(20-580) MMP14:TIMP2:proMMP2KLKB1(20-390) MMP13(20-54)MMP13ELANE MMP7(95-267) MMP15 MMP16 proMT-MMPsMMP11KLKB1(20-390) MMP13 intermediateformsMMP13(20-76)proMMP1 initialactivatorsMMP13(77-103) TIMP2COL18A1(1572-11754)MMP2(110-660) MMP3(55-477)MMP9(60-106)MMP3(100-477) MMP14:TIMP2CHS TIMP2 MMP3(100-477)KLKB1(391-638) KLK2 CTRB2(167-263) MMP15(42-669) MMP3(100-477) MMP2(110-660) MMP14 CTRB1(167-263) MMP1(54-83)KLK2 TIMP1 MMP2(30-66)KLKB1(391-638) MMP7(18-50)MMP13(55-471)MMP14 (16)MMP15 MMP11(32-488)CTRB1(19-31) CTRB1(34-164) PRSS1(24-247) MMP7(95-267) CTRB2(34-164) PLG(581-810) MMP7(18-94)COL18A1(1572-11754)PRSS2(24-247) MMP13(58-471)Trypsin, plasmin MMP3(55-99)MMP1(100-469)CTRB2(19-31) Trypsin, plasminTIMP2 MMP7(95-267) proMMP8 initialactivatorsCTSG MMP14(21-582) PRSS1(24-247) ELANE MMP8(21-467)PLG(581-810) MMP25 MMP24(53-645) MMP13(77-471) PLG(20-580) MMP1,7MMP13(58-471) MMP10(18-476)MMP7 initialactivatorsMMP14MMP3(100-477) 294329


The matrix metalloproteinases (MMPs), previously known as matrixins, are classically known to be involved in the turnover of extracellular matrix (ECM) components. However, recent high throughput proteomics analyses have revealed that ~80% of MMP substrates are non-ECM proteins including cytokines, growth factor binding protiens, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signalling, and that some MMPs are beneficial and may be drug anti-targets. Thus, MMPs have important roles in many processes including embryo development, morphogenesis, tissue homeostasis and remodeling. They are implicated in several diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes. Alternate splice forms are known, leading to nuclear localization of select MMPs. Most are secreted from the cell, or in the case of membrane type (MT) MMPs become plasma membrane associated, as inactive proenzymes. Their subsequent activation is a key regulatory step, with requirements specific to MMP subtype. View original pathway at Reactome.


Pathway is converted from Reactome ID: 1592389
Reactome version: 75
Reactome Author 
Reactome Author: Jupe, Steve

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  1. Sorsa T, Salo T, Koivunen E, Tyynelä J, Konttinen YT, Bergmann U, Tuuttila A, Niemi E, Teronen O, Heikkilä P, Tschesche H, Leinonen J, Osman S, Stenman UH.; ''Activation of type IV procollagenases by human tumor-associated trypsin-2.''; PubMed Europe PMC Scholia
  2. Nakamura H, Fujii Y, Ohuchi E, Yamamoto E, Okada Y.; ''Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases.''; PubMed Europe PMC Scholia
  3. Butler GS, Overall CM.; ''Updated biological roles for matrix metalloproteinases and new "intracellular" substrates revealed by degradomics.''; PubMed Europe PMC Scholia
  4. Nagase H, Enghild JJ, Suzuki K, Salvesen G.; ''Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate.''; PubMed Europe PMC Scholia
  5. Cauwe B, Van den Steen PE, Opdenakker G.; ''The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases.''; PubMed Europe PMC Scholia
  6. Imai K, Yokohama Y, Nakanishi I, Ohuchi E, Fujii Y, Nakai N, Okada Y.; ''Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties.''; PubMed Europe PMC Scholia
  7. Suzuki K, Lees M, Newlands GF, Nagase H, Woolley DE.; ''Activation of precursors for matrix metalloproteinases 1 (interstitial collagenase) and 3 (stromelysin) by rat mast-cell proteinases I and II.''; PubMed Europe PMC Scholia
  8. Crabbe T, Willenbrock F, Eaton D, Hynds P, Carne AF, Murphy G, Docherty AJ.; ''Biochemical characterization of matrilysin. Activation conforms to the stepwise mechanisms proposed for other matrix metalloproteinases.''; PubMed Europe PMC Scholia
  9. Goldberg GI, Strongin A, Collier IE, Genrich LT, Marmer BL.; ''Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin.''; PubMed Europe PMC Scholia
  10. Morrison CJ, Butler GS, Rodríguez D, Overall CM.; ''Matrix metalloproteinase proteomics: substrates, targets, and therapy.''; PubMed Europe PMC Scholia
  11. Capodici C, Muthukumaran G, Amoruso MA, Berg RA.; ''Activation of neutrophil collagenase by cathepsin G.''; PubMed Europe PMC Scholia
  12. Nagase H, Ogata Y, Suzuki K, Enghild JJ, Salvesen G.; ''Substrate specificities and activation mechanisms of matrix metalloproteinases.''; PubMed Europe PMC Scholia
  13. Knäuper V, López-Otin C, Smith B, Knight G, Murphy G.; ''Biochemical characterization of human collagenase-3.''; PubMed Europe PMC Scholia
  14. Murphy G, Bretz U, Baggiolini M, Reynolds JJ.; ''The latent collagenase and gelatinase of human polymorphonuclear neutrophil leucocytes.''; PubMed Europe PMC Scholia
  15. Suzuki K, Nagase H, Ito A, Enghild JJ, Salvesen G.; ''The role of matrix metalloproteinase 3 in the stepwise activation of human rheumatoid synovial procollagenase.''; PubMed Europe PMC Scholia
  16. Strongin AY, Marmer BL, Grant GA, Goldberg GI.; ''Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2.''; PubMed Europe PMC Scholia
  17. Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI.; ''Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease.''; PubMed Europe PMC Scholia
  18. Rodríguez D, Morrison CJ, Overall CM.; ''Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics.''; PubMed Europe PMC Scholia
  19. Crabbe T, O'Connell JP, Smith BJ, Docherty AJ.; ''Reciprocated matrix metalloproteinase activation: a process performed by interstitial collagenase and progelatinase A.''; PubMed Europe PMC Scholia
  20. Crabbe T, Smith B, O'Connell J, Docherty A.; ''Human progelatinase A can be activated by matrilysin.''; PubMed Europe PMC Scholia
  21. Knäuper V, Krämer S, Reinke H, Tschesche H.; ''Characterization and activation of procollagenase from human polymorphonuclear leucocytes. N-terminal sequence determination of the proenzyme and various proteolytically activated forms.''; PubMed Europe PMC Scholia
  22. Knäuper V, Smith B, López-Otin C, Murphy G.; ''Activation of progelatinase B (proMMP-9) by active collagenase-3 (MMP-13).''; PubMed Europe PMC Scholia
  23. Kang T, Nagase H, Pei D.; ''Activation of membrane-type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi network.''; PubMed Europe PMC Scholia
  24. Sopata I, Dancewicz AM.; ''Presence of a gelatin-specific proteinase and its latent form in human leucocytes.''; PubMed Europe PMC Scholia
  25. Tschesche H, Michaelis J, Kohnert U, Fedrowitz J, Oberhoff R.; ''Tissue kallikrein effectively activates latent matrix degrading metalloenzymes.''; PubMed Europe PMC Scholia
  26. Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H.; ''Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin).''; PubMed Europe PMC Scholia
  27. Sang QX, Birkedal-Hansen H, Van Wart HE.; ''Proteolytic and non-proteolytic activation of human neutrophil progelatinase B.''; PubMed Europe PMC Scholia
  28. Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M.; ''Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2.''; PubMed Europe PMC Scholia
  29. Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMed Europe PMC Scholia
  30. Ogata Y, Enghild JJ, Nagase H.; ''Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9.''; PubMed Europe PMC Scholia
  31. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M.; ''A matrix metalloproteinase expressed on the surface of invasive tumour cells.''; PubMed Europe PMC Scholia
  32. Nagase H, Suzuki K, Morodomi T, Enghild JJ, Salvesen G.; ''Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3.''; PubMed Europe PMC Scholia
  33. Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI.; ''SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages.''; PubMed Europe PMC Scholia
  34. Atkinson SJ, Crabbe T, Cowell S, Ward RV, Butler MJ, Sato H, Seiki M, Reynolds JJ, Murphy G.; ''Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes.''; PubMed Europe PMC Scholia
  35. Fridman R, Toth M, Peña D, Mobashery S.; ''Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2).''; PubMed Europe PMC Scholia
  36. Pei D, Weiss SJ.; ''Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity.''; PubMed Europe PMC Scholia
  37. Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d'Ortho MP, Murphy G.; ''The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study.''; PubMed Europe PMC Scholia
  38. Kinoshita T, Sato H, Okada A, Ohuchi E, Imai K, Okada Y, Seiki M.; ''TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads.''; PubMed Europe PMC Scholia
  39. Okada Y, Morodomi T, Enghild JJ, Suzuki K, Yasui A, Nakanishi I, Salvesen G, Nagase H.; ''Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties.''; PubMed Europe PMC Scholia
  40. Okada Y, Harris ED, Nagase H.; ''The precursor of a metalloendopeptidase from human rheumatoid synovial fibroblasts. Purification and mechanisms of activation by endopeptidases and 4-aminophenylmercuric acetate.''; PubMed Europe PMC Scholia
  41. Knäuper V, Will H, López-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM, Murphy G.; ''Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme.''; PubMed Europe PMC Scholia
  42. Santavicca M, Noel A, Angliker H, Stoll I, Segain JP, Anglard P, Chretien M, Seidah N, Basset P.; ''Characterization of structural determinants and molecular mechanisms involved in pro-stromelysin-3 activation by 4-aminophenylmercuric acetate and furin-type convertases.''; PubMed Europe PMC Scholia
  43. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed Europe PMC Scholia
  44. Pei D, Weiss SJ.; ''Furin-dependent intracellular activation of the human stromelysin-3 zymogen.''; PubMed Europe PMC Scholia


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114688view16:16, 25 January 2021ReactomeTeamReactome version 75
113134view11:19, 2 November 2020ReactomeTeamReactome version 74
112292view15:12, 9 October 2020ReactomeTeamReactome version 73
101267view11:15, 1 November 2018ReactomeTeamreactome version 66
100805view20:44, 31 October 2018ReactomeTeamreactome version 65
100347view19:21, 31 October 2018ReactomeTeamreactome version 64
99892view16:04, 31 October 2018ReactomeTeamreactome version 63
99449view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93485view11:24, 9 August 2017ReactomeTeamreactome version 61
86581view09:21, 11 July 2016ReactomeTeamreactome version 56
83201view10:21, 18 November 2015ReactomeTeamVersion54
81581view13:07, 21 August 2015ReactomeTeamVersion53
77041view08:34, 17 July 2014ReactomeTeamFixed remaining interactions
76746view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76071view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75781view11:30, 10 June 2014ReactomeTeamReactome 48 Update
75131view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74778view08:51, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
CHS MetaboliteCHEBI:37397 (ChEBI)
CMA1 ProteinP23946 (Uniprot-TrEMBL)
COL18A1(1572-11754)ProteinP39060 (Uniprot-TrEMBL)
CTRB1(167-263) ProteinP17538 (Uniprot-TrEMBL)
CTRB1(19-31) ProteinP17538 (Uniprot-TrEMBL)
CTRB1(34-164) ProteinP17538 (Uniprot-TrEMBL)
CTRB2(167-263) ProteinQ6GPI1 (Uniprot-TrEMBL)
CTRB2(19-31) ProteinQ6GPI1 (Uniprot-TrEMBL)
CTRB2(34-164) ProteinQ6GPI1 (Uniprot-TrEMBL)
CTSG ProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
CTSK ProteinP43235 (Uniprot-TrEMBL)
CTSL2 ProteinO60911 (Uniprot-TrEMBL)
ELANE ProteinP08246 (Uniprot-TrEMBL)
FURINProteinP09958 (Uniprot-TrEMBL)
Heparins MetaboliteCHEBI:24505 (ChEBI)
Highly sulphated glycosaminoglycansComplexR-ALL-1604783 (Reactome)
KLK2 ProteinP20151 (Uniprot-TrEMBL)
KLKB1(20-390) ProteinP03952 (Uniprot-TrEMBL)
KLKB1(391-638) ProteinP03952 (Uniprot-TrEMBL)
MMP1 (2, 3, 7, 10, 13)ComplexR-HSA-1604697 (Reactome)
MMP1(100-469) ProteinP03956 (Uniprot-TrEMBL)
MMP1(100-469)ProteinP03956 (Uniprot-TrEMBL)
MMP1(20-469)ProteinP03956 (Uniprot-TrEMBL)
MMP1(20-53)ProteinP03956 (Uniprot-TrEMBL)
MMP1(54-469)ProteinP03956 (Uniprot-TrEMBL)
MMP1(54-83)ProteinP03956 (Uniprot-TrEMBL)
MMP1(84-469)ProteinP03956 (Uniprot-TrEMBL)
MMP1,7ComplexR-HSA-1604358 (Reactome)
MMP10 ProteinP09238 (Uniprot-TrEMBL)
MMP10(18-476)ProteinP09238 (Uniprot-TrEMBL)
MMP10ProteinP09238 (Uniprot-TrEMBL)
MMP11 ProteinP24347 (Uniprot-TrEMBL)
MMP11(32-488)ProteinP24347 (Uniprot-TrEMBL)
MMP11ProteinP24347 (Uniprot-TrEMBL)
MMP13 ProteinP45452 (Uniprot-TrEMBL)
MMP13 intermediate form fragmentsComplexR-HSA-1604745 (Reactome)
MMP13 intermediate formsComplexR-HSA-1604714 (Reactome)
MMP13(20-471)ProteinP45452 (Uniprot-TrEMBL)
MMP13(20-54)ProteinP45452 (Uniprot-TrEMBL)
MMP13(20-57)ProteinP45452 (Uniprot-TrEMBL)
MMP13(20-76)ProteinP45452 (Uniprot-TrEMBL)
MMP13(55-103) ProteinP45452 (Uniprot-TrEMBL)
MMP13(55-471) ProteinP45452 (Uniprot-TrEMBL)
MMP13(55-471)ProteinP45452 (Uniprot-TrEMBL)
MMP13(58-103) ProteinP45452 (Uniprot-TrEMBL)
MMP13(58-471) ProteinP45452 (Uniprot-TrEMBL)
MMP13(58-471)ProteinP45452 (Uniprot-TrEMBL)
MMP13(77-103) ProteinP45452 (Uniprot-TrEMBL)
MMP13(77-471) ProteinP45452 (Uniprot-TrEMBL)
MMP13(77-471)ProteinP45452 (Uniprot-TrEMBL)
MMP13ProteinP45452 (Uniprot-TrEMBL)
MMP14 (16)ComplexR-HSA-1629856 (Reactome)
MMP14 ProteinP50281 (Uniprot-TrEMBL)
MMP14(21-582) ProteinP50281 (Uniprot-TrEMBL)
MMP14:TIMP2:MMP2 intermediate formComplexR-HSA-1604373 (Reactome)
MMP14:TIMP2:proMMP2ComplexR-HSA-1604369 (Reactome)
MMP14:TIMP2ComplexR-HSA-1604365 (Reactome)
MMP14:TIMP:MMP2ComplexR-HSA-1604349 (Reactome)
MMP14ProteinP50281 (Uniprot-TrEMBL)
MMP15 ProteinP51511 (Uniprot-TrEMBL)
MMP15(42-669) ProteinP51511 (Uniprot-TrEMBL)
MMP16 ProteinP51512 (Uniprot-TrEMBL)
MMP16(32-607) ProteinP51512 (Uniprot-TrEMBL)
MMP17(126-?) ProteinQ9ULZ9 (Uniprot-TrEMBL)
MMP17(36-?) ProteinQ9ULZ9 (Uniprot-TrEMBL)
MMP2(110-660) ProteinP08253 (Uniprot-TrEMBL)
MMP2(110-660)ProteinP08253 (Uniprot-TrEMBL)
MMP2(30-66)ProteinP08253 (Uniprot-TrEMBL)
MMP2(30-660) ProteinP08253 (Uniprot-TrEMBL)
MMP2(30-660)ProteinP08253 (Uniprot-TrEMBL)
MMP2(67-109)ProteinP08253 (Uniprot-TrEMBL)
MMP2(67-660) ProteinP08253 (Uniprot-TrEMBL)
MMP2(67-660)ProteinP08253 (Uniprot-TrEMBL)
MMP2,3,7,10,11ComplexR-HSA-1604372 (Reactome)
MMP24(156-?) ProteinQ9Y5R2 (Uniprot-TrEMBL)
MMP24(53-645) ProteinQ9Y5R2 (Uniprot-TrEMBL)
MMP25 ProteinQ9NPA2 (Uniprot-TrEMBL)
MMP25(22-?) ProteinQ9NPA2 (Uniprot-TrEMBL)
MMP3(100-477) ProteinP08254 (Uniprot-TrEMBL)
MMP3(100-477)ProteinP08254 (Uniprot-TrEMBL)
MMP3(18-477)ProteinP08254 (Uniprot-TrEMBL)
MMP3(18-54)ProteinP08254 (Uniprot-TrEMBL)
MMP3(55-477)ProteinP08254 (Uniprot-TrEMBL)
MMP3(55-99)ProteinP08254 (Uniprot-TrEMBL)
MMP3, CTSK, CTSL2ComplexR-HSA-2514830 (Reactome)
MMP7 initial activatorsComplexR-HSA-1604762 (Reactome)
MMP7(18-267)ProteinP09237 (Uniprot-TrEMBL)
MMP7(18-50)ProteinP09237 (Uniprot-TrEMBL)
MMP7(18-94)ProteinP09237 (Uniprot-TrEMBL)
MMP7(51-267)ProteinP09237 (Uniprot-TrEMBL)
MMP7(51-94)ProteinP09237 (Uniprot-TrEMBL)
MMP7(95-267) ProteinP09237 (Uniprot-TrEMBL)
MMP7(95-267)ProteinP09237 (Uniprot-TrEMBL)
MMP8(21-467)ProteinP22894 (Uniprot-TrEMBL)
MMP8ProteinP22894 (Uniprot-TrEMBL)
MMP9(107-707)ProteinP14780 (Uniprot-TrEMBL)
MMP9(20-106)ProteinP14780 (Uniprot-TrEMBL)
MMP9(20-59)ProteinP14780 (Uniprot-TrEMBL)
MMP9(20-707) ProteinP14780 (Uniprot-TrEMBL)
MMP9(20-707)ProteinP14780 (Uniprot-TrEMBL)
MMP9(60-106)ProteinP14780 (Uniprot-TrEMBL)
MMP9(60-707)ProteinP14780 (Uniprot-TrEMBL)
MT-MMPsComplexR-HSA-1604727 (Reactome)
MT-MMPsComplexR-HSA-1605821 (Reactome)
PLG(20-580) ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810) ProteinP00747 (Uniprot-TrEMBL)
PRSS1(24-247) ProteinP07477 (Uniprot-TrEMBL)
PRSS2(24-247) ProteinP07478 (Uniprot-TrEMBL)
SPOCK3ProteinQ9BQ16 (Uniprot-TrEMBL)
TIMP1 ProteinP01033 (Uniprot-TrEMBL)
TIMP1ProteinP01033 (Uniprot-TrEMBL)
TIMP2 ProteinP16035 (Uniprot-TrEMBL)
TIMP2ProteinP16035 (Uniprot-TrEMBL)
TPSAB1 ProteinQ15661 (Uniprot-TrEMBL)
Trypsin, plasmin R-HSA-1604696 (Reactome)
Trypsin, plasminComplexR-HSA-1604696 (Reactome)
proMMP1 initial activatorsComplexR-HSA-1602468 (Reactome)
proMMP10 activatorsComplexR-HSA-2127633 (Reactome)
proMMP3 initial activatorsComplexR-HSA-1604721 (Reactome)
proMMP8 initial activatorsComplexR-HSA-2127623 (Reactome)
proMMP9 activating proteasesComplexR-HSA-1604717 (Reactome)
proMMP9:TIMP1ComplexR-HSA-1604377 (Reactome)
proMT-MMPsComplexR-HSA-1604700 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
COL18A1(1572-11754)TBarR-HSA-1592278 (Reactome)
COL18A1(1572-11754)TBarR-HSA-1604722 (Reactome)
COL18A1(1572-11754)TBarR-HSA-1604732 (Reactome)
FURINmim-catalysisR-HSA-1602466 (Reactome)
FURINmim-catalysisR-HSA-1602484 (Reactome)
Highly sulphated glycosaminoglycansArrowR-HSA-1604763 (Reactome)
MMP1 (2, 3, 7, 10, 13)mim-catalysisR-HSA-1592436 (Reactome)
MMP1 (2, 3, 7, 10, 13)mim-catalysisR-HSA-1604690 (Reactome)
MMP1(100-469)ArrowR-HSA-1592297 (Reactome)
MMP1(20-469)R-HSA-1592316 (Reactome)
MMP1(20-53)ArrowR-HSA-1592316 (Reactome)
MMP1(54-469)ArrowR-HSA-1592316 (Reactome)
MMP1(54-469)R-HSA-1602473 (Reactome)
MMP1(54-469)mim-catalysisR-HSA-1602473 (Reactome)
MMP1(54-83)ArrowR-HSA-1602473 (Reactome)
MMP1(84-469)ArrowR-HSA-1602473 (Reactome)
MMP1(84-469)R-HSA-1592297 (Reactome)
MMP1,7mim-catalysisR-HSA-1604359 (Reactome)
MMP10(18-476)R-HSA-1602458 (Reactome)
MMP10ArrowR-HSA-1602458 (Reactome)
MMP11(32-488)R-HSA-1602484 (Reactome)
MMP11ArrowR-HSA-1602484 (Reactome)
MMP13 intermediate form fragmentsArrowR-HSA-1604732 (Reactome)
MMP13 intermediate formsR-HSA-1604732 (Reactome)
MMP13 intermediate formsmim-catalysisR-HSA-1604732 (Reactome)
MMP13(20-471)R-HSA-1602488 (Reactome)
MMP13(20-471)R-HSA-1604741 (Reactome)
MMP13(20-471)R-HSA-1604752 (Reactome)
MMP13(20-54)ArrowR-HSA-1604741 (Reactome)
MMP13(20-57)ArrowR-HSA-1602488 (Reactome)
MMP13(20-76)ArrowR-HSA-1604752 (Reactome)
MMP13(55-471)ArrowR-HSA-1604741 (Reactome)
MMP13(58-471)ArrowR-HSA-1602488 (Reactome)
MMP13(77-471)ArrowR-HSA-1604752 (Reactome)
MMP13ArrowR-HSA-1604732 (Reactome)
MMP14 (16)mim-catalysisR-HSA-1604360 (Reactome)
MMP14 (16)mim-catalysisR-HSA-1604741 (Reactome)
MMP14:TIMP2:MMP2 intermediate formArrowR-HSA-1604360 (Reactome)
MMP14:TIMP2:MMP2 intermediate formR-HSA-1604368 (Reactome)
MMP14:TIMP2:MMP2 intermediate formmim-catalysisR-HSA-1604368 (Reactome)
MMP14:TIMP2:proMMP2ArrowR-HSA-1604350 (Reactome)
MMP14:TIMP2:proMMP2R-HSA-1604360 (Reactome)
MMP14:TIMP2ArrowR-HSA-1592349 (Reactome)
MMP14:TIMP2R-HSA-1604350 (Reactome)
MMP14:TIMP:MMP2ArrowR-HSA-1604368 (Reactome)
MMP14R-HSA-1592349 (Reactome)
MMP2(110-660)ArrowR-HSA-1592278 (Reactome)
MMP2(30-66)ArrowR-HSA-1604359 (Reactome)
MMP2(30-66)ArrowR-HSA-1604360 (Reactome)
MMP2(30-660)R-HSA-1604350 (Reactome)
MMP2(30-660)R-HSA-1604359 (Reactome)
MMP2(67-109)ArrowR-HSA-1592278 (Reactome)
MMP2(67-109)ArrowR-HSA-1604368 (Reactome)
MMP2(67-660)ArrowR-HSA-1604359 (Reactome)
MMP2(67-660)R-HSA-1592278 (Reactome)
MMP2(67-660)mim-catalysisR-HSA-1592278 (Reactome)
MMP2,3,7,10,11mim-catalysisR-HSA-1592297 (Reactome)
MMP3(100-477)ArrowR-HSA-1604731 (Reactome)
MMP3(18-477)R-HSA-1592371 (Reactome)
MMP3(18-54)ArrowR-HSA-1592371 (Reactome)
MMP3(55-477)ArrowR-HSA-1592371 (Reactome)
MMP3(55-477)R-HSA-1604731 (Reactome)
MMP3(55-477)mim-catalysisR-HSA-1604731 (Reactome)
MMP3(55-99)ArrowR-HSA-1604731 (Reactome)
MMP3, CTSK, CTSL2mim-catalysisR-HSA-1592362 (Reactome)
MMP3, CTSK, CTSL2mim-catalysisR-HSA-1604752 (Reactome)
MMP7 initial activatorsmim-catalysisR-HSA-1604712 (Reactome)
MMP7(18-267)R-HSA-1592362 (Reactome)
MMP7(18-267)R-HSA-1604712 (Reactome)
MMP7(18-50)ArrowR-HSA-1604712 (Reactome)
MMP7(18-94)ArrowR-HSA-1592362 (Reactome)
MMP7(51-267)ArrowR-HSA-1604712 (Reactome)
MMP7(51-267)R-HSA-1604763 (Reactome)
MMP7(51-267)mim-catalysisR-HSA-1604763 (Reactome)
MMP7(51-94)ArrowR-HSA-1604763 (Reactome)
MMP7(95-267)ArrowR-HSA-1592362 (Reactome)
MMP7(95-267)ArrowR-HSA-1604763 (Reactome)
MMP8(21-467)R-HSA-1592398 (Reactome)
MMP8ArrowR-HSA-1592398 (Reactome)
MMP9(107-707)ArrowR-HSA-1604690 (Reactome)
MMP9(107-707)ArrowR-HSA-1604722 (Reactome)
MMP9(20-106)ArrowR-HSA-1604722 (Reactome)
MMP9(20-59)ArrowR-HSA-1592436 (Reactome)
MMP9(20-707)R-HSA-1592436 (Reactome)
MMP9(20-707)R-HSA-1602454 (Reactome)
MMP9(20-707)R-HSA-1604722 (Reactome)
MMP9(60-106)ArrowR-HSA-1604690 (Reactome)
MMP9(60-707)ArrowR-HSA-1592436 (Reactome)
MMP9(60-707)R-HSA-1604690 (Reactome)
MT-MMPsArrowR-HSA-1602466 (Reactome)
MT-MMPsArrowR-HSA-1605825 (Reactome)
MT-MMPsR-HSA-1605825 (Reactome)
R-HSA-1592278 (Reactome) Cleaving the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). This activation is inhibited by endostatin (Nyberg et al. 2003). Residue numbering here refers to the UniProt canonical sequence.
R-HSA-1592297 (Reactome) The 42 kDa intermediate form of MMP1 is fully activated by cleavage of the Gln99-Phe100 bond, producing a 41 kDa protein. MMP2 (Crabbe et al. 1994), MMP3 (Suzuki et al. 1990, Nagase et al. 1992), MMP7 (Imai et al. 1995), MMP10 (Nicholson et al. 1989) and MMP11 (Murphy et al. 1993) are able to convert the 42 kDa intermediate to fully activated 41 kDa form though they are not able to initiate activation of proMMP1 effectively (Nagase et al. 1992). MMP3 regulates MMP1 collagenase activity in human rheumatoid synovial fibroblasts (Unemori et al. 1991).
R-HSA-1592316 (Reactome) ProMMP1 has several activators including plasmin (Eeckhout & Vaes 1977, Werb et al. 1977, Santala et al. 1999), trypsin (Grant et al. 1987, Saunders et al. 2005), plasma kallikrein (Nagase et al. 1982, Saunders et al. 2005), chymase (Saarinen et al. 1994, Suzuki et al. 1995, Saunders et al. 2005), tryptase (Gruber et al. 1989, Suzuki et al. 1995, Saunders et al. 2005), neutrophil elastase, cathepsin G (Saunders et al. 2005) and trypsin-2 (Moilanen et al. 2003). Concanavalin A (ConA) was the first cellular treatment that yielded active MMPs in culture, inducing the cellular activation of MMP1 likely through MMP14 activity (Overall and Sodek 1990).Trypsin-like serine proteinases are believed to remove 34-36 residues from the N-terminus of the secreted pro-enzyme, equivalent to positions 53-55 of the UniProt cannonical sequence which includes a signal peptide. Removal of this region is sufficient to destabilize the Cys92-Zn2+ stabilizing bond (numbered according to the Uniprot canonical sequence, Cys73 when numbered from the N terminus of the secreted peptide as typically represented in the literature) and partially activate enzyme activity. This intermediate form then undergoes autocatalysis at Thr83-Leu84 producing an MMP1 with about 20% of full collagenase activity (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. When first reported, considerable debate surrounded the activation of this archetypical MMP. Divergence of opinion resulted when competing groups studied activation in vitro using chemicals (organomercurials such as aminophenylmecuricacetate), which yield a different autolytic cleavage site in the protease susceptible loop when compared with the site cut by serine proteases such as trypsin. Different specific activities result, but in general the final autolytic cleavage site for all MMPs is the homologous Phe or Tyr at position 100 or 101. When the active enzyme commences here, full activity is realised due to the salt bridge forming between the N-terminal primary amine of the conserved Phe or Tyr with an Asp on helix C that in turn salt bridges to the active site Glu. Termini either side of this position do not result in full activity.
R-HSA-1592349 (Reactome) MMP14 (MT1-MMP) binds tissue inhibitor of metalloproteinases 2 (TIMP2) and has been isolated as a complex from the plasma membrane of HT-1080 cells (Strongin et al. 1995). This complex in turn binds proMMP2 via an interaction of the C-termini of proMMP2 and TIMP2 (Itoh et al. 1998, Butler et al. 1998). Formation of this ternary complex is critical for the subsequent activation of proMMP2.
R-HSA-1592362 (Reactome) MMP3 activates MMP7 by cleavage of Glu94-Tyr95 (Imai et al. 1997).
R-HSA-1592371 (Reactome) proMMP3 is activated in a similar manner to pro MMP1 but by a large number of proteinases, including bacterial thermolysin, all cleaving within the region residues 51-56 (Woessner & Nagase 2000). This initiates autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence.
R-HSA-1592398 (Reactome) proMMP8 is activated by tissue kallikrein, leukocyte elastase, trypsin and cathepsin G (Capodici et al. 1989, Knauper et al. 1990) probably at the predicted bait region, residues 30-36.
R-HSA-1592436 (Reactome) MMP1 (Sang et al. 1995), MMP2 (Fridman et al. 1995), MMP3 (Goldberg et al. 1992, Ogata et al. 1992, Okada et al. 1992), MMP7 (Imai et al. 1995, Sang et al. 1995), MMP10 (Nakamura et al. 1998) and MMP13 (Knauper et al. 1997) activate MMP9 by a stepwise mechanism but the second cleavage is apparently not an autocatalytic event as is the case for MMP1 (Okada et al. 1992). The first site is the Glu59-Met60 bond, generating an inactive 85-86 kDa intermediate (O'Connell et al. 1994), followed by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82 kDa form of MMP9 (Okada et al. 1992, Fridman et al. 1995).
R-HSA-1602454 (Reactome) ProMMP9 binds Tissue Inhibitor of Metalloproteinases 1 (TIMP1) (Wilheim et al. 1989). By homology with the binding of TIMP2 to the MMP2 hemopexin domain, TIMP1 is thought to binds via its C domain to the MMP9 hemopexin domain. This is a two-way potential regulatory mechanism as the interaction does not prevent the free N-terminal inhibitory domain of TIMP1 from inhibiting other MMPs (Murthpy et al. 1991) while it may prevent the activation of proMMP9.
R-HSA-1602458 (Reactome) proMMP10 is similar in sequence to proMMP3 with just one residue difference in the bait region. The activation mechanism is believed to be similar, namely cleavage in the N-terminal bait region, followed by autocatalytic cleavage at His81-Phe82 (Woessner & Nagasse 2000). proMMP10 is activated by plasmin, trypsin and chymotrypsin.
R-HSA-1602466 (Reactome) The membrane-type MMPs (MT-MMPs) MMP14 (MT1-MMP) (Pei et al. 1996, Sato et al. 1996) and MMP16 (MT3-MMP) (Kang et al. 2002) are processed to an active form by furin (Yana & Weiss 2000) and PACE4 (Bassi et al. 2005) within the golgi before secretion. The other MT-MMPs MMP15 (MT2-MMP), MMP17 (MT4-MMP) (Itoh et al. 1999), MMP24 (MT5-MMP) and MMP25 (MT6-MMP) (Starr et al. 2012) are believed to undergo similar processing before membrane association.
R-HSA-1602473 (Reactome) Following initiating proteolytic cleavage by serine proteases the Cys92-Zn2+ bond is destabilized allowing autocleavage at Thr83-Leu84, generating a 42 kDa active form of MMP1 with about 20% of the activity of the 41 kDa form (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100.
R-HSA-1602484 (Reactome) proMMP11 has a furin recognition sequence and is activated by furin in the Golgi (Pei & Weiss 1996, Santavicca et al. 1996).
R-HSA-1602488 (Reactome) proMMP13 can be activated by plasmin and trypsin initially cleaving at Lys57-Glu58 followed by autoproteolysis at Glu103-Tyr104 (Knauper et al. 1996a).
R-HSA-1604350 (Reactome) The MMP14:TIMP2 complex can efficiently bind proMMP2. Physiological concentrations of TIMP2 enhance proMMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that while MMP14:TIMP2 complexes bind proMMP2, local free MMP14 cleaves the TIMP-bound proMMP2 in the prodomain, leading to autoactivation between Asn109 Tyr110. In vivo the majority of MMP14 (MT1-MMP) is bound to TIMP2 and therefore functions as a receptor for proMMP2 (Nishida et al. 2008). Binding of TIMP-2 to proMMP2 occurs via interaction of the TIMP2 C domain (McQuibban et al. 2000) and the MMP2 hemopexin domain between hemopexin blades III and IV (Overall et al. 1999) in an interaction that is highly dependant upon the nature of the C-tail of the TIMP (Kai et al. 2002). TIMP-4 also binds the proMMP2 hemopexin domain (Bigg et al. 1997) to prevent activation by MMP14 (Bigg et al. 2001). An alternative cell surface localization mechanism exists that inhibits MMP2 activation: Cell surface Beta1 integrin binds native type I collagen, which in turn is bound by the fibronectin type II modules of MMP2 to prevent activation by MMP14 (Steffensen et al. 1998).
R-HSA-1604359 (Reactome) MMP2 can be activated by MMP1 (Crabbe et al. 1994a, Sang et al. 1996) and MMP7 (Crabbe et al. 1994b, Sang et al. 1996). MMP1 initially cleaves either Pro33-Ile34 or Asn66-Leu67. This is followed by autolytic cleavage at Asn109-Tyr110 (Crabbe et al. 1994a, Okada et al. 1990, Sang et al. 1996). MMP1 and MMP7 are not efficient activators of MMP2; significant physiological activation of proMMP2 is performed by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997, Morrison et al. 2001) and MMP16 (Takino et al. 1995). Residue numbering here refers to the UniProt canonical sequence.
R-HSA-1604360 (Reactome) MMP2 is activated by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997) and MMP16 (Takino et al. 1995). MMP14 (MT1-MMP) initially cleaves the Asn66-Leu67 bond of MMP2, followed by autocleavage of the Asn109-Tyr110 bond (Strongin et al. 1993, Atkinson et al. 1995). Residue numbering here refers to the UniProt canonical sequence.

MMP2 processing by MMP14 or MMP16 is very inefficient unless the MT-MMP has pre-bound TIMP2, which in turn binds MMP2. Physiological concentrations of TIMP2 enhance MMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that MT-MMP:TIMP2 complexes bind MMP2, but local free MT-MMP subsequently cleaves the TIMP-bound proMMP2. In vivo the majority of MMP14 is bound to TIMP2 and functions as a receptor for proMMP2 (Nishida et al. 2008). In contrast, activation of proMMP2 by MMP15 occurs in a TIMP independent manner, with TIMP2 inhibiting activation at all concentrations (Morrison et al. 2001). Native type I collagen binds to the hemopexin C domain of MMP14, and following clustering of the enzyme together enhances proMMP2 activation (Tam et al. 2002). However, proMMP2 also binds the cell via cell surface Beta1 integrin, which binds native type I collagen which in turn is bound by the fibronectin type II modules of MMP2, preventing activation by MMP14 (Steffensen et al. 1998). ConA is the only known stimulator of cells to induce proMMP2 activation by MMP14 (Overall & Sodek 1990).
R-HSA-1604368 (Reactome) Cleavage of the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). Residue numbering here refers to the UniProt canonical sequence.
R-HSA-1604690 (Reactome) The intermediate form of MMP9 is activated by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82-kDa MMP-9 species (Ogata et al. 1992, Fridman et al. 1995).
R-HSA-1604712 (Reactome) proMMP7 (proMatrilysin-1) activation by trypsin occurs via an intermediate cleaved at Lys50-Asn51 which undergoes autocatalysis (Crabbe et al. 1992). Leukocyte elastase and plasmin partially activate MMP7 by an uncharacterized mechanism. Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009).
R-HSA-1604722 (Reactome) proMMP9 can be activated by trypsin and chymotrypsin (Sopata & Dancewicz 1974), tissue kallikrein (Tschesche et al. 1989, Desrivieres et al. 1993), cathepsin G (Murphy et al. 1980), and trypsin-2 (Sorsa et al. 1997). This appears to be a one-step activation; the single peptide bond cleaved by trypsin-2 in proMMP-9 is Arg106-Phe107. Modes of activation by other proteases are unclear. Activation is inhibited by endostatin (Nyberg et al. 2003).
R-HSA-1604731 (Reactome) After the initial cleavage of the N-terminus, MMP3 undergoes autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence.
R-HSA-1604732 (Reactome) Following initial activation autoproteolysis occurs at Glu103-Tyr104 (Knauper et al. 1996a,1996b). This is inhibited by endostatin (Nyberg et al. 2003).
R-HSA-1604741 (Reactome) MMP14 (MT1-MMP) initially cleaves MMP13 at Gly54-Ile55 (Knauper et al. 1996a, 1996b) followed by autoprocessing at Glu103-Tyr104.
R-HSA-1604752 (Reactome) MMP3 initially cleaves proMMP13 at Gly76-Leu77 followed by autoprocessing at Glu103-Tyr104 (Knauper et al. 1996).
R-HSA-1604763 (Reactome) Once cleaved at Lys50-Asn51 MMP7 undergoes autocatalysis (Crabbe et al. 1992). Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009).
R-HSA-1605825 (Reactome) The process that targets activated MT-MMPs to the plasma membrane is unclear but presumed to involve standard golgi transport mechanisms. The cytoplasmic domain of MT1-MMP is critical for the localization to discrete regions of the cell surface (Urena et al. 1999) and involved in internalization which has a regulatory role. The cytoplasmic domain mediates interactions with specific cell-surface proteins such as C1Q binding protein which may serve to direct the MMP from the golgi to the cell surface (Rozanov et al. 2002).
SPOCK3TBarR-HSA-1604360 (Reactome)
TIMP1R-HSA-1602454 (Reactome)
TIMP2R-HSA-1592349 (Reactome)
Trypsin, plasminmim-catalysisR-HSA-1602488 (Reactome)
proMMP1 initial activatorsmim-catalysisR-HSA-1592316 (Reactome)
proMMP10 activatorsmim-catalysisR-HSA-1602458 (Reactome)
proMMP3 initial activatorsmim-catalysisR-HSA-1592371 (Reactome)
proMMP8 initial activatorsmim-catalysisR-HSA-1592398 (Reactome)
proMMP9 activating proteasesmim-catalysisR-HSA-1604722 (Reactome)
proMMP9:TIMP1ArrowR-HSA-1602454 (Reactome)
proMT-MMPsR-HSA-1602466 (Reactome)
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