Degradation of the extracellular matrix (Homo sapiens)

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Bibliography

1. Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV.; ''BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan.''; PubMed Europe PMC Scholia
2. Fukai F, Ohtaki M, Fujii N, Yajima H, Ishii T, Nishizawa Y, Miyazaki K, Katayama T.; ''Release of biological activities from quiescent fibronectin by a conformational change and limited proteolysis by matrix metalloproteinases.''; PubMed Europe PMC Scholia
3. 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
4. Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L.; ''Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin).''; PubMed Europe PMC Scholia
5. Truebestein L, Tennstaedt A, Mönig T, Krojer T, Canellas F, Kaiser M, Clausen T, Ehrmann M.; ''Substrate-induced remodeling of the active site regulates human HTRA1 activity.''; PubMed Europe PMC Scholia
6. Zack MD, Malfait AM, Skepner AP, Yates MP, Griggs DW, Hall T, Hills RL, Alston JT, Nemirovskiy OV, Radabaugh MR, Leone JW, Arner EC, Tortorella MD.; ''ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala(271).''; PubMed Europe PMC Scholia
7. Samanna V, Wei H, Ego-Osuala D, Chellaiah MA.; ''Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells.''; PubMed Europe PMC Scholia
8. Chamberland A, Wang E, Jones AR, Collins-Racie LA, LaVallie ER, Huang Y, Liu L, Morris EA, Flannery CR, Yang Z.; ''Identification of a novel HtrA1-susceptible cleavage site in human aggrecan: evidence for the involvement of HtrA1 in aggrecan proteolysis in vivo.''; PubMed Europe PMC Scholia
9. Xiong W, Knispel R, MacTaggart J, Greiner TC, Weiss SJ, Baxter BT.; ''Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo.''; PubMed Europe PMC Scholia
10. Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS.; ''Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor.''; PubMed Europe PMC Scholia
11. Campbell RL, Davies PL.; ''Structure-function relationships in calpains.''; PubMed Europe PMC Scholia
12. Lu P, Takai K, Weaver VM, Werb Z.; ''Extracellular matrix degradation and remodeling in development and disease.''; PubMed Europe PMC Scholia
13. Taleb S, Cancello R, Clément K, Lacasa D.; ''Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation.''; PubMed Europe PMC Scholia
14. Sorimachi H, Hata S, Ono Y.; ''Expanding members and roles of the calpain superfamily and their genetically modified animals.''; PubMed Europe PMC Scholia
15. Cailhier JF, Sirois I, Laplante P, Lepage S, Raymond MA, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hébert MJ.; ''Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis.''; PubMed Europe PMC Scholia
16. Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P.; ''ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.''; PubMed Europe PMC Scholia
17. Croall DE, Ersfeld K.; ''The calpains: modular designs and functional diversity.''; PubMed Europe PMC Scholia
18. 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
19. Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y.; ''Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites.''; PubMed Europe PMC Scholia
20. Morrison CJ, Butler GS, Rodríguez D, Overall CM.; ''Matrix metalloproteinase proteomics: substrates, targets, and therapy.''; PubMed Europe PMC Scholia
21. Hindson VJ, Ashworth JL, Rock MJ, Cunliffe S, Shuttleworth CA, Kielty CM.; ''Fibrillin degradation by matrix metalloproteinases: identification of amino- and carboxy-terminal cleavage sites.''; PubMed Europe PMC Scholia
22. Johnson SK, Ramani VC, Hennings L, Haun RS.; ''Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin.''; PubMed Europe PMC Scholia
23. Wu BT, Su YH, Tsai MT, Wasserman SM, Topper JN, Yang RB.; ''A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones.''; PubMed Europe PMC Scholia
24. Udayakumar TS, Chen ML, Bair EL, Von Bredow DC, Cress AE, Nagle RB, Bowden GT.; ''Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration.''; PubMed Europe PMC Scholia
25. Shapiro SD, Kobayashi DK, Ley TJ.; ''Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages.''; PubMed Europe PMC Scholia
26. Mimura T, Han KY, Onguchi T, Chang JH, Kim TI, Kojima T, Zhou Z, Azar DT.; ''MT1-MMP-mediated cleavage of decorin in corneal angiogenesis.''; PubMed Europe PMC Scholia
27. Najy AJ, Day KC, Day ML.; ''The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation.''; PubMed Europe PMC Scholia
28. Vartio T.; ''Characterization of the binding domains in the fragments cleaved by cathepsin G from human plasma fibronectin.''; PubMed Europe PMC Scholia
29. Butler GS, Overall CM.; ''Updated biological roles for matrix metalloproteinases and new "intracellular" substrates revealed by degradomics.''; PubMed Europe PMC Scholia
30. Nakada M, Miyamori H, Kita D, Takahashi T, Yamashita J, Sato H, Miura R, Yamaguchi Y, Okada Y.; ''Human glioblastomas overexpress ADAMTS-5 that degrades brevican.''; PubMed Europe PMC Scholia
31. Shi F, Sottile J.; ''MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin.''; PubMed Europe PMC Scholia
32. Ahmed N, Pansino F, Clyde R, Murthi P, Quinn MA, Rice GE, Agrez MV, Mok S, Baker MS.; ''Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade.''; PubMed Europe PMC Scholia
33. Kirschner R, Hubmacher D, Iyengar G, Kaur J, Fagotto-Kaufmann C, Brömme D, Bartels R, Reinhardt DP.; ''Classical and neonatal Marfan syndrome mutations in fibrillin-1 cause differential protease susceptibilities and protein function.''; PubMed Europe PMC Scholia
34. Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M.; ''HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins.''; PubMed Europe PMC Scholia
35. Goll DE, Thompson VF, Li H, Wei W, Cong J.; ''The calpain system.''; PubMed Europe PMC Scholia
36. Symowicz J, Adley BP, Gleason KJ, Johnson JJ, Ghosh S, Fishman DA, Hudson LG, Stack MS.; ''Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells.''; PubMed Europe PMC Scholia
37. Sorimachi H, Hata S, Ono Y.; ''Calpain chronicle--an enzyme family under multidisciplinary characterization.''; PubMed Europe PMC Scholia
38. 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
39. Knäuper V, Cowell S, Smith B, López-Otin C, O'Shea M, Morris H, Zardi L, Murphy G.; ''The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction.''; PubMed Europe PMC Scholia
40. Stracke JO, Hutton M, Stewart M, Pendás AM, Smith B, López-Otin C, Murphy G, Knäuper V.; ''Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme.''; PubMed Europe PMC Scholia
41. Guo H, Li R, Zucker S, Toole BP.; ''EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface.''; PubMed Europe PMC Scholia
42. Wu YY, Peck K, Chang YL, Pan SH, Cheng YF, Lin JC, Yang RB, Hong TM, Yang PC.; ''SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer.''; PubMed Europe PMC Scholia
43. Lettau I, Hattermann K, Held-Feindt J, Brauer R, Sedlacek R, Mentlein R.; ''Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells.''; PubMed Europe PMC Scholia
44. Murphy G, Cockett MI, Ward RV, Docherty AJ.; ''Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP).''; PubMed Europe PMC Scholia
45. Shapiro SD.; ''Matrix metalloproteinase degradation of extracellular matrix: biological consequences.''; PubMed Europe PMC Scholia
46. Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD, Shuttleworth CA, Kielty CM.; ''Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.''; PubMed Europe PMC Scholia
47. Imai K, Hiramatsu A, Fukushima D, Pierschbacher MD, Okada Y.; ''Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release.''; PubMed Europe PMC Scholia
48. Ono Y, Sorimachi H.; ''Calpains: an elaborate proteolytic system.''; PubMed Europe PMC Scholia
49. Hu SI, Carozza M, Klein M, Nantermet P, Luk D, Crowl RM.; ''Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage.''; PubMed Europe PMC Scholia
50. Toole BP.; ''Hyaluronan and its binding proteins, the hyaladherins.''; PubMed Europe PMC Scholia
51. Li T, Ma G, Cai H, Price DL, Wong PC.; ''Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals.''; PubMed Europe PMC Scholia
52. d'Ortho MP, Will H, Atkinson S, Butler G, Messent A, Gavrilovic J, Smith B, Timpl R, Zardi L, Murphy G.; ''Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases.''; PubMed Europe PMC Scholia
53. Tío L, Martel-Pelletier J, Pelletier JP, Bishop PN, Roughley P, Farran A, Benito P, Monfort J.; ''Characterization of opticin digestion by proteases involved in osteoarthritis development.''; PubMed Europe PMC Scholia
54. Hadler-Olsen E, Fadnes B, Sylte I, Uhlin-Hansen L, Winberg JO.; ''Regulation of matrix metalloproteinase activity in health and disease.''; PubMed Europe PMC Scholia
55. Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA.; ''The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases.''; PubMed Europe PMC Scholia
56. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC Scholia
57. Steinhusen U, Weiske J, Badock V, Tauber R, Bommert K, Huber O.; ''Cleavage and shedding of E-cadherin after induction of apoptosis.''; PubMed Europe PMC Scholia
58. Velasco G, Cal S, Quesada V, Sánchez LM, López-Otín C.; ''Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins.''; PubMed Europe PMC Scholia
59. Gronski TJ, Martin RL, Kobayashi DK, Walsh BC, Holman MC, Huber M, Van Wart HE, Shapiro SD.; ''Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
A2M	Protein	P01023 (Uniprot-TrEMBL)
A2M tetramer	Complex	R-HSA-158255 (Reactome)
ADAM10, ADAM15	Protein	R-HSA-4224013 (Reactome)
ADAM8	Protein	P78325 (Uniprot-TrEMBL)
ADAMTS4, 5, (1, 8, 9, 16, 18)	Protein	R-HSA-3791133 (Reactome)
ADAMTS4, ADAMTS5	Protein	R-HSA-3828053 (Reactome)
Activation of Matrix Metalloproteinases	Pathway	R-HSA-1592389 (Reactome)	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.
Active caspase-3 heterotetramer, calpain-1	Complex	R-HSA-3828019 (Reactome)
Aggrecan(17-360)	Protein	R-HSA-3814822 (Reactome)
Aggrecan(17-392)	Protein	R-HSA-3791320 (Reactome)
Aggrecan(361-2415)	Protein	R-HSA-3814815 (Reactome)
Aggrecan(393-2415)	Protein	R-HSA-3791316 (Reactome)
Aggrecan	Protein	R-HSA-2318622 (Reactome)
Alpha 2-macroglobulin:MMP1, 3, 13, (2, 7-12, 19)	Complex	R-HSA-2559501 (Reactome)
BMP1, TLL1, TLL2, Cathepsin L1	Protein	R-HSA-3828023 (Reactome)
BSG	Protein	P35613 (Uniprot-TrEMBL)
BSG:MMP1(100-469)	Complex	R-HSA-375089 (Reactome)
BSG	Protein	P35613 (Uniprot-TrEMBL)
Brevican(23-360)	Protein	R-HSA-3791183 (Reactome)
Brevican(23-395)	Protein	R-HSA-3791124 (Reactome)
Brevican(361-911)	Protein	R-HSA-3791187 (Reactome)
Brevican(396-911)	Protein	R-HSA-3791150 (Reactome)
Brevican	Protein	R-HSA-2681671 (Reactome)
CAPN1	Protein	P07384 (Uniprot-TrEMBL)
CAPNS1	Protein	P04632 (Uniprot-TrEMBL)
CASP3(176-277)	Protein	P42574 (Uniprot-TrEMBL)
CASP3(29-175)	Protein	P42574 (Uniprot-TrEMBL)
CD44	Protein	P16070 (Uniprot-TrEMBL)
CD44:MMP2, MMP7, MMP9	Complex	R-HSA-2559499 (Reactome)
CD44	Protein	P16070 (Uniprot-TrEMBL)
CDH1(155-700)	Protein	P12830 (Uniprot-TrEMBL)
CDH1(155-750)	Protein	P12830 (Uniprot-TrEMBL)
CDH1(155-882)	Protein	P12830 (Uniprot-TrEMBL)
CDH1(155-882):Ca2+ dimer	Complex	R-HSA-2534182 (Reactome)
CDH1(701-882)	Protein	P12830 (Uniprot-TrEMBL)
CDH1(732-882)	Protein	P12830 (Uniprot-TrEMBL)
CDH1(751-882)	Protein	P12830 (Uniprot-TrEMBL)
CTSG	Protein	P08311 (Uniprot-TrEMBL)	After secretion Cathepsin G is extracellular and associated with the plasma membrane.
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Cleaved elastin		R-HSA-2514799 (Reactome)
Cleaved fibrillin 1,2,(3)		R-HSA-2514788 (Reactome)
Cleaved fibrillin-1		R-HSA-2514812 (Reactome)
Cleaved fibronectin matrix Ala(271)/Val(272)		R-HSA-3787944 (Reactome)
Cleaved fibronectin matrix		R-HSA-2533900 (Reactome)
Cleaved laminin-332	Complex	R-HSA-2533911 (Reactome)
Collagen degradation	Pathway	R-HSA-1442490 (Reactome)	Collagen fibril diameter and spatial organisation are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005). The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010). Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner. Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).
DCN(31-?)	Protein	P07585 (Uniprot-TrEMBL)
DCN(?-359)	Protein	P07585 (Uniprot-TrEMBL)
DCN	Protein	P07585 (Uniprot-TrEMBL)
E-cadherin strand dimer fragment 155-700	Complex	R-HSA-2534301 (Reactome)
E-cadherin strand dimer fragment 155-750	Complex	R-HSA-3827963 (Reactome)
E-cadherin strand dimer fragment 701-882	Complex	R-HSA-2534305 (Reactome)
E-cadherin strand dimer fragment 732-882	Complex	R-HSA-3828003 (Reactome)
E-cadherin strand dimer fragment 751-882	Complex	R-HSA-3828004 (Reactome)
ELANE	Protein	P08246 (Uniprot-TrEMBL)
Elastin-degrading extracellular proteinases	Protein	R-HSA-2514800 (Reactome)
Elastin		R-HSA-2161232 (Reactome)
Fibrillin 1,2,(3)		R-HSA-2159839 (Reactome)
Fibrillin-1		R-HSA-2159874 (Reactome)
Fibronectin matrix		R-HSA-2327729 (Reactome)
HSPG2(22-4196)	Protein	P98160 (Uniprot-TrEMBL)
HSPG2(22-4391)	Protein	P98160 (Uniprot-TrEMBL)
HSPG2(22-?)	Protein	P98160 (Uniprot-TrEMBL)
HSPG2(4197-4391)	Protein	P98160 (Uniprot-TrEMBL)
HSPG2(?-4391)	Protein	P98160 (Uniprot-TrEMBL)
LAMA3	Protein	Q16787 (Uniprot-TrEMBL)
LAMA3(36-?)	Protein	Q16787 (Uniprot-TrEMBL)
LAMA3(?-3333)	Protein	Q16787 (Uniprot-TrEMBL)
LAMA5	Protein	O15230 (Uniprot-TrEMBL)
LAMA5(36-?)	Protein	O15230 (Uniprot-TrEMBL)
LAMA5(?-3695)	Protein	O15230 (Uniprot-TrEMBL)
LAMB1	Protein	P07942 (Uniprot-TrEMBL)
LAMB3	Protein	Q13751 (Uniprot-TrEMBL)
LAMB3(18-?)	Protein	Q13751 (Uniprot-TrEMBL)
LAMB3(?-1172)	Protein	Q13751 (Uniprot-TrEMBL)
LAMC1	Protein	P11047 (Uniprot-TrEMBL)
LAMC2	Protein	Q13753 (Uniprot-TrEMBL)
LAMC2(22-?)	Protein	Q13753 (Uniprot-TrEMBL)
LAMC2(?-1193)	Protein	Q13753 (Uniprot-TrEMBL)
Laminin-332 degrading extracellular proteinases	Protein	R-HSA-3788041 (Reactome)
Laminin-332	Complex	R-HSA-216001 (Reactome)
Laminin-511 (cleaved alpha chain)	Complex	R-HSA-3791167 (Reactome)
Laminin-511	Complex	R-HSA-2328098 (Reactome)
MMP1(100-469)	Protein	P03956 (Uniprot-TrEMBL)
MMP1(100-469)	Protein	P03956 (Uniprot-TrEMBL)
MMP1, 2, 3, 7,8,10,13,19	Protein	R-HSA-3791153 (Reactome)
MMP1, 3, 13, (2, 7-12, 19)	Protein	R-HSA-2559551 (Reactome)
MMP1, 3, 7, 12, 13, 19, CTSS	Protein	R-HSA-2533895 (Reactome)
MMP1, MMP9, MMP12, ELANE	Protein	R-HSA-2533968 (Reactome)
MMP1,2,3,7,9,12,13	Protein	R-HSA-3814814 (Reactome)
MMP10	Protein	P09238 (Uniprot-TrEMBL)
MMP13, CTSS	Protein	R-HSA-2534222 (Reactome)
MMP14, MMP15	Protein	R-HSA-1605832 (Reactome)
MMP14	Protein	P50281 (Uniprot-TrEMBL)
MMP19	Protein	Q99542 (Uniprot-TrEMBL)
MMP2(110-660)	Protein	P08253 (Uniprot-TrEMBL)
MMP2, MMP3, MMP7	Protein	R-HSA-2534228 (Reactome)
MMP2, MMP7, MMP9	Protein	R-HSA-2559546 (Reactome)
MMP2,9,12,13	Protein	R-HSA-2514778 (Reactome)
MMP3, CTSK, CTSL2	Protein	R-HSA-2514830 (Reactome)
MMP3, MMP7, Plasmin	Protein	R-HSA-2534258 (Reactome)
MMP3, MMP7	Protein	R-HSA-2533973 (Reactome)
MMP3, plasmin, (MMP12)	Protein	R-HSA-2534177 (Reactome)
MMP7	Protein	P09237 (Uniprot-TrEMBL)
MMP9	Protein	P14780 (Uniprot-TrEMBL)
MMP9, KLK7	Protein	R-HSA-3827999 (Reactome)
NCSTN	Protein	Q92542 (Uniprot-TrEMBL)
NID1(29-?)	Protein	P14543 (Uniprot-TrEMBL)
NID1(?-1247)	Protein	P14543 (Uniprot-TrEMBL)
NID1	Protein	P14543 (Uniprot-TrEMBL)
PS1:NCSTN	Complex	R-HSA-2534270 (Reactome)
PSEN1(1-298)	Protein	P49768 (Uniprot-TrEMBL)
PSEN1(299-467)	Protein	P49768 (Uniprot-TrEMBL)
SPP1(17-?)	Protein	P10451 (Uniprot-TrEMBL)
SPP1(?-314)	Protein	P10451 (Uniprot-TrEMBL)
SPP1	Protein	P10451 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
A2M tetramer			R-HSA-1454781 (Reactome)
ADAM10, ADAM15		mim-catalysis	R-HSA-4224014 (Reactome)
ADAM8		mim-catalysis	R-HSA-3788061 (Reactome)
ADAMTS4, 5, (1, 8, 9, 16, 18)		mim-catalysis	R-HSA-1592310 (Reactome)
ADAMTS4, ADAMTS5		mim-catalysis	R-HSA-3788075 (Reactome)
Active caspase-3 heterotetramer, calpain-1		mim-catalysis	R-HSA-2534260 (Reactome)
	Aggrecan(17-360)	Arrow	R-HSA-3791295 (Reactome)
	Aggrecan(17-392)	Arrow	R-HSA-1592310 (Reactome)
	Aggrecan(361-2415)	Arrow	R-HSA-3791295 (Reactome)
	Aggrecan(393-2415)	Arrow	R-HSA-1592310 (Reactome)
Aggrecan			R-HSA-1592310 (Reactome)
Aggrecan			R-HSA-3791295 (Reactome)
	Alpha 2-macroglobulin:MMP1, 3, 13, (2, 7-12, 19)	Arrow	R-HSA-1454781 (Reactome)
BMP1, TLL1, TLL2, Cathepsin L1		mim-catalysis	R-HSA-3814820 (Reactome)
	BSG:MMP1(100-469)	Arrow	R-HSA-1454838 (Reactome)
BSG			R-HSA-1454838 (Reactome)
	Brevican(23-360)	Arrow	R-HSA-3791149 (Reactome)
	Brevican(23-395)	Arrow	R-HSA-3788075 (Reactome)
	Brevican(361-911)	Arrow	R-HSA-3791149 (Reactome)
	Brevican(396-911)	Arrow	R-HSA-3788075 (Reactome)
Brevican			R-HSA-3788075 (Reactome)
Brevican			R-HSA-3791149 (Reactome)
	CD44:MMP2, MMP7, MMP9	Arrow	R-HSA-1454791 (Reactome)
CD44			R-HSA-1454791 (Reactome)
CDH1(155-882):Ca2+ dimer			R-HSA-1454843 (Reactome)
CDH1(155-882):Ca2+ dimer			R-HSA-2534206 (Reactome)
CDH1(155-882):Ca2+ dimer			R-HSA-2534260 (Reactome)
CDH1(155-882):Ca2+ dimer			R-HSA-3827958 (Reactome)
CDH1(155-882):Ca2+ dimer			R-HSA-4224014 (Reactome)
CTSG		mim-catalysis	R-HSA-3785684 (Reactome)
	Cleaved elastin	Arrow	R-HSA-1566962 (Reactome)
	Cleaved elastin	Arrow	R-HSA-2514790 (Reactome)
	Cleaved fibrillin 1,2,(3)	Arrow	R-HSA-2485148 (Reactome)
	Cleaved fibrillin-1	Arrow	R-HSA-2514772 (Reactome)
	Cleaved fibrillin-1	Arrow	R-HSA-2514823 (Reactome)
	Cleaved fibrillin-1	Arrow	R-HSA-2514831 (Reactome)
	Cleaved fibronectin matrix Ala(271)/Val(272)	Arrow	R-HSA-3788061 (Reactome)
	Cleaved fibronectin matrix	Arrow	R-HSA-1566981 (Reactome)
	Cleaved fibronectin matrix	Arrow	R-HSA-2533944 (Reactome)
	Cleaved fibronectin matrix	Arrow	R-HSA-2533950 (Reactome)
	Cleaved fibronectin matrix	Arrow	R-HSA-3785684 (Reactome)
	Cleaved laminin-332	Arrow	R-HSA-1566979 (Reactome)
	Cleaved laminin-332	Arrow	R-HSA-3791155 (Reactome)
	DCN(31-?)	Arrow	R-HSA-2534248 (Reactome)
	DCN(31-?)	Arrow	R-HSA-3828025 (Reactome)
	DCN(?-359)	Arrow	R-HSA-2534248 (Reactome)
	DCN(?-359)	Arrow	R-HSA-3828025 (Reactome)
DCN			R-HSA-2534248 (Reactome)
DCN			R-HSA-3828025 (Reactome)
	E-cadherin strand dimer fragment 155-700	Arrow	R-HSA-1454843 (Reactome)
	E-cadherin strand dimer fragment 155-700	Arrow	R-HSA-3827958 (Reactome)
	E-cadherin strand dimer fragment 155-700	Arrow	R-HSA-4224014 (Reactome)
	E-cadherin strand dimer fragment 155-750	Arrow	R-HSA-2534206 (Reactome)
	E-cadherin strand dimer fragment 155-750	Arrow	R-HSA-2534260 (Reactome)
	E-cadherin strand dimer fragment 701-882	Arrow	R-HSA-1454843 (Reactome)
	E-cadherin strand dimer fragment 701-882	Arrow	R-HSA-3827958 (Reactome)
	E-cadherin strand dimer fragment 701-882	Arrow	R-HSA-4224014 (Reactome)
	E-cadherin strand dimer fragment 732-882	Arrow	R-HSA-2534206 (Reactome)
	E-cadherin strand dimer fragment 751-882	Arrow	R-HSA-2534260 (Reactome)
ELANE		mim-catalysis	R-HSA-2514823 (Reactome)
Elastin-degrading extracellular proteinases		mim-catalysis	R-HSA-1566962 (Reactome)
Elastin			R-HSA-1566962 (Reactome)
Elastin			R-HSA-2514790 (Reactome)
Fibrillin 1,2,(3)			R-HSA-2485148 (Reactome)
Fibrillin-1			R-HSA-2514772 (Reactome)
Fibrillin-1			R-HSA-2514823 (Reactome)
Fibrillin-1			R-HSA-2514831 (Reactome)
Fibronectin matrix			R-HSA-1566981 (Reactome)
Fibronectin matrix			R-HSA-2533944 (Reactome)
Fibronectin matrix			R-HSA-2533950 (Reactome)
Fibronectin matrix			R-HSA-3785684 (Reactome)
Fibronectin matrix			R-HSA-3788061 (Reactome)
	HSPG2(22-4196)	Arrow	R-HSA-3814820 (Reactome)
HSPG2(22-4391)			R-HSA-1592314 (Reactome)
HSPG2(22-4391)			R-HSA-2534160 (Reactome)
HSPG2(22-4391)			R-HSA-2534240 (Reactome)
HSPG2(22-4391)			R-HSA-3814820 (Reactome)
	HSPG2(22-?)	Arrow	R-HSA-1592314 (Reactome)
	HSPG2(22-?)	Arrow	R-HSA-2534160 (Reactome)
	HSPG2(22-?)	Arrow	R-HSA-2534240 (Reactome)
	HSPG2(4197-4391)	Arrow	R-HSA-3814820 (Reactome)
	HSPG2(?-4391)	Arrow	R-HSA-1592314 (Reactome)
	HSPG2(?-4391)	Arrow	R-HSA-2534160 (Reactome)
	HSPG2(?-4391)	Arrow	R-HSA-2534240 (Reactome)
Laminin-332 degrading extracellular proteinases		mim-catalysis	R-HSA-1566979 (Reactome)
Laminin-332			R-HSA-1566979 (Reactome)
Laminin-332			R-HSA-3791155 (Reactome)
	Laminin-511 (cleaved alpha chain)	Arrow	R-HSA-2533874 (Reactome)
Laminin-511			R-HSA-2533874 (Reactome)
MMP1(100-469)			R-HSA-1454838 (Reactome)
MMP1, 2, 3, 7,8,10,13,19		mim-catalysis	R-HSA-3791149 (Reactome)
MMP1, 3, 13, (2, 7-12, 19)			R-HSA-1454781 (Reactome)
MMP1, 3, 7, 12, 13, 19, CTSS		mim-catalysis	R-HSA-1566981 (Reactome)
MMP1, MMP9, MMP12, ELANE		mim-catalysis	R-HSA-1592270 (Reactome)
MMP1,2,3,7,9,12,13		mim-catalysis	R-HSA-3791295 (Reactome)
MMP10		mim-catalysis	R-HSA-2533944 (Reactome)
MMP13, CTSS		mim-catalysis	R-HSA-2534160 (Reactome)
MMP14, MMP15		mim-catalysis	R-HSA-2533965 (Reactome)
MMP14, MMP15		mim-catalysis	R-HSA-2534240 (Reactome)
MMP14		mim-catalysis	R-HSA-2514790 (Reactome)
MMP14		mim-catalysis	R-HSA-2514831 (Reactome)
MMP14		mim-catalysis	R-HSA-2533874 (Reactome)
MMP14		mim-catalysis	R-HSA-2533950 (Reactome)
MMP14		mim-catalysis	R-HSA-3791155 (Reactome)
MMP14		mim-catalysis	R-HSA-3828025 (Reactome)
MMP19		mim-catalysis	R-HSA-3791319 (Reactome)
MMP2, MMP3, MMP7		mim-catalysis	R-HSA-2534248 (Reactome)
MMP2, MMP7, MMP9			R-HSA-1454791 (Reactome)
MMP2,9,12,13		mim-catalysis	R-HSA-2485148 (Reactome)
MMP3, CTSK, CTSL2		mim-catalysis	R-HSA-2514772 (Reactome)
MMP3, MMP7, Plasmin		mim-catalysis	R-HSA-1454843 (Reactome)
MMP3, MMP7		mim-catalysis	R-HSA-2533970 (Reactome)
MMP3, MMP7		mim-catalysis	R-HSA-4086205 (Reactome)
MMP3, plasmin, (MMP12)		mim-catalysis	R-HSA-1592314 (Reactome)
MMP9, KLK7		mim-catalysis	R-HSA-3827958 (Reactome)
	NID1(29-?)	Arrow	R-HSA-1592270 (Reactome)
	NID1(29-?)	Arrow	R-HSA-2533965 (Reactome)
	NID1(29-?)	Arrow	R-HSA-2533970 (Reactome)
	NID1(29-?)	Arrow	R-HSA-3791319 (Reactome)
	NID1(?-1247)	Arrow	R-HSA-1592270 (Reactome)
	NID1(?-1247)	Arrow	R-HSA-2533965 (Reactome)
	NID1(?-1247)	Arrow	R-HSA-2533970 (Reactome)
	NID1(?-1247)	Arrow	R-HSA-3791319 (Reactome)
NID1			R-HSA-1592270 (Reactome)
NID1			R-HSA-2533965 (Reactome)
NID1			R-HSA-2533970 (Reactome)
NID1			R-HSA-3791319 (Reactome)
PS1:NCSTN		mim-catalysis	R-HSA-2534206 (Reactome)
			R-HSA-1454781 (Reactome)	Alpha 2-macroglobulin (A2M) is a plasma glycoprotein consisting of 4 near-identical subunits (Andersen et al. 1995). A2M inhibits almost all endopeptidases regardless of their specificities (Barrett 1981). A2M binding to an endopeptidase is triggered by cleavage of a peptide bond in the 'bait region' of A2M, triggering a conformational change in A2M that in turn entraps the peptidase without blocking the active site (Barrett & Starkey 1973). This blocks enzyme activity against large protein substrates while not preventing activity on low molecular weight substrates. Once bound, A2M-proteinase complexes are endocytosed by low density lipoprotein receptor-related protein-1 (LRP1) (Strickland et al. 1990). Active metalloproteinases (MMPs) that can be entrapped by A2M include MMP3 (Enghild et al. 1989) MMP1 (Grinnell et al. 1998) and MMP 13 (Beekman et al. 1999). The significance of this mechanism as a regulator of MMP activity is unclear (Baker et al. 2002, Nagase et al. 2006).
			R-HSA-1454791 (Reactome)	Certain normally extracellular MMPs can transiently localize at the cell periphery in association with adhesion receptors or proteoglycans. ProMMP9, MMP9, MMP2 and MMP7 (Ahmed et al. 2002, Samanna et al. 2006, Yu et al. 2002) localize at the cell membrane with the single-pass transmembrane glycoprotein CD44, known to be involved in hyaluronan-cell interactions, lymphocyte homing and cell adhesion (Toole 1990). Membrane-associated MMP7 can bring about the shedding of several membrane proteins such as epidermal growth factor (EGF), soluble Fas ligand (FasL), E-cadherin and TNF-alpha from their membrane-bound precursors, thereby promoting cancer progression (Li et al. 2006). MMP9 is able to cleave CD44, inhibiting cell migration and reducing the malignant potential of tumour cells (Chetty et al. 2012).
			R-HSA-1454838 (Reactome)	BSG (CD147, EMMPRIN) is a glycoprotein, enriched on the surface of tumor cells. It stimulates production of matrix metalloproteinases by adjacent stromal cells. It forms a complex with MMP1 at the cell surface.
			R-HSA-1454843 (Reactome)	E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.
			R-HSA-1566962 (Reactome)	The elastin component of elastic fibres is degraded to soluble fragments by MMP2 (Murphy et al. 1991), MMP7 (Quantin et al. 1989, Murphy et al. 1991), MMP9 (Murphy et al. 1991, Katsuda et al. 1994) and MMP12 (macrophage elastase) (Shapiro et al. 1993, Taddese et al. 2008), and to a limited extent by MMP3 and 10 (Murphy et al. 1991). In addition, elastin is a substrate for neutrophil elastase (Reilly & Travis 1980). Eighty-nine tropoelastin cleavage sites were identified for MMP-12, whereas MMP-7 and MMP-9 were found to cleave at only 58 and 63 sites, respectively (Heinz et al. 2010).
			R-HSA-1566979 (Reactome)	Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Keratinocytes of the skin secrete numerous laminin isoforms, including laminin-511 and laminin-332. Laminin-332 undergoes extensive proteolysis following secretion, which is essential for laminin-332 integration into the BM (Rousselle & Beck 2013). The 200 kDa alpha-3 subunit of laminin-332 is cleaved between the LG3-LG4 subdomains to generate a 165 kDa product. The 160 kDa gamma-2 subunit is cleaved at its N-terminus to produce a 105 kDa protein (Marinkovich et al. 1992). Tissue remodeling may lead to further proteolysis of the 105 kDa subunit within the N-terminus giving rise to a 80 kDa protein (Gianelli et al. 1997, Koshikawa et al. 2005). The resulting N-terminal fragment has EGF-like properties and may activate the EGF receptor, inducing cell migration (Schenk et al. 2003). In much of the early literature it is not clear which subunit of the laminin trimer was cleaved, but in vitro studies have revealed specific enzymes involved in the processing of laminin-332 including MMP2, MMP14 (MT1-MMP), and the C-proteinase family of enzymes, especially bone morphogenic protein 1 (BMP1) and mammalian tolloid (mTLD), isoforms 1 and 3 respectively of UniProt P13497 BMP1 (Sugawara et al. 2008, Rousselle & Beck 2013). Many proteases have been demonstrated to degrade specific subunits of laminin-332. The beta-3 chain is degraded by matrix metalloproteinase 14 (MMP14, MT1-MMP, Udayakumar et al. 2003) and MMP7 (Remy et al. 2006). The alpha-3 chain is degraded by plasmin (Goldfinger et al. 1998, 1999) and BMP1 (and its isoform mTLD, Veitch et al. 2003). Laminin gamma-2 chain is degraded by MMP14 (Koshikawa et al. 2000, 2005, Pirilä et al. 2003) , MMP2 (Gianelli et al. 1997, Pirilä et al. 2003), MMP3, 12, 13 (Pirilä et al. 2003), 19 (Sadowski et al. 2005), MMP20 (Väänänen et al. 2001, Pirilä et al. 2003), BMP1 (Amano et al. 2000, Kessler et al. 2001) and mTLD (Veitch et al. 2003). Plasmin cleavage of laminin-111 yields fragments with sizes that correspond to the cleavage of the alpha and beta/gamma components (Gutiérrez-Fernández et al. 2009). In this reaction laminin-322 is represented with all 3 component peptides cleaved.
			R-HSA-1566981 (Reactome)	MMP1 can degrade fibronectin (Fukai et al. 1995), as can MMP3 (Gunja-Smith et al. 1985, Nicholson et al. 1989, Wilhelm et al. 1993, Fukai et al. 1995), MMP7 (Quantin et al. 1989, Miyazaki et al. 1990, Fukai et al. 1995, von Bredow et al. 1995), MMP10 (Nicholson et al. 1989), MMP12 (Gronski et al. 1997), MMP13 (Knauper et al. 1997), MMP14 (Shi & Sottile 2011) and 19 (Stracke et al. 2000). Cathepsin S is able to degrade fibronectin (Taleb et al. 2006). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) suggesting that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004).
			R-HSA-1592270 (Reactome)	Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
			R-HSA-1592310 (Reactome)	Aggrecan (large aggregating proteoglycan, chondroitin sulfate proteoglycan 1) is a major structural component of cartilage, particularly articular cartilage. The core protein has over 100 chains of chondroitin sulphate and keratan sulphate giving a MWt of about 250 kDa. The core protein has 2 N-terminal globular domains G1 and G2 and a C-terminal globular G3 domain. G2 and G3 are separated by a region heavily modified with negatively charged glycosaminoglycans (GAGs). The two main modifier moieties keratan sulfate (KS) and chondroitin sulfate (CS) are arranged into two CS regions and a KS-rich region. The 15-kDa interglobular linker (IGD) between the N-terminal G1 and G2 domains is particularly susceptible to proteolysis (Caterson et al. 2000). Degradation in this region is associated with the development of osteoarthritis (Troeberg & Nagase 2012). Members of the ADAM (A Disintegrin And Metalloprotease) protein family are responsible for this cleavage (East et al. 2007, Huang & Wu 2008). Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn341~Phe342 bond (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as others towards the C-terminus. However, the the majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala373 (numbered here according to the UniProt sequence, these residues referred to as Glu373-Ala374 in most literature) in the IGD (Sandy et al. 1992). ADAMTS5 (aggrecanase-2, Abbaszade et al. 1999) and to a lesser extent ADAMTS4 (aggrecanase-1, Tortorella et al. 1999) are primarrily responsible (Gendron et al. 2007) though the preferred cleavage sites of these are in the CS-2 domain. ADAMTS1 (Kuno et al. 2000, Rodriques-Manzaneque et al. 2002), 9, (Somerville et al. 2003), 8 (Colins-Racie 2004), 16 and 18 (Zeng et al. 2006) can also degrade aggrecan in vitro.
			R-HSA-1592314 (Reactome)	HSPG2 protein (perlecan) consists of a core protein of molecular weight 470 kDa with three long glycosaminoglycan (GAG) chains attached, each approximately 70-100 kDa. These are usually heparan sulphate (HS), but can be chondroitin sulphate (CS). The core protein consists of five distinct structural domains. The N-terminal domain I (aa ~1-195) contains attachment sites for GAG chains. Although GAG chains are not required for correct folding and secretion of the protein, lack of GAG or decreased sulfation can decrease perlecan's ability to interact with matrix proteins. Removal of GAG chains may affect matrix organization and endothelial barrier function. The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. For example, HS-bound FGF was released from cultured cells by treatments with MMP3, rat MMP13, and plasmin (Whitelock et al. 1996). Other MMPs reported to degrade HSPG2 include MMP14 and MMP15 (d'Ortho et al. 1997). MMP12 releases chondroitin sulphate and heparan sulphate from basement membranes (Gronski et al. 1997) and degrades the related aggrecan (Durigova et al. 2011) so may degrade perlecan. Corneal epithelium explant growth correlates with MMP2 expression, an initial degradation of the original basement membrane, and an initial upregulation followed by downregulation of MMP9. However this may not result from direct cleavage of HSPG2 by these MMPs, they may modulate some factor involved in the maturation of basement membrane (Li et al. 2006). The core protein of HSPG2 can be cleaved by cathepsin S (Liuzzo et al. 1999).
			R-HSA-2485148 (Reactome)	All mammals have three fibrillin genes (Davis & Summers 2012). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. Fibrillin-1 is the major structural component of microfibrils (Kielty et al. 2005). Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 was isolated from and is predominantly expressed in brain; it is not known whether it forms microfibrils (Corson et al. 2004). Fibrillin-1 and -2 are degraded by MMP2, 9, 12 and 13 (Ashworth et al. 1999, Hindson et al. 1999). Fibrillin-1 is additionally degraded by MMP3 (Ashworth et al. 1999), the membrane-associated MMP14 (Ashworth et al. 1999), neutrophil elastase (ELANE) (Kielty et al. 1994), cathepsin L2 (V) and cathepsin K (Kirschner et al. 2011).
			R-HSA-2514772 (Reactome)	Fibrillin-1 can be degraded by MMP3 (Ashworth et al. 1999) and cathepsins K and L2 (V) (Kirschner et al. 2011).
			R-HSA-2514790 (Reactome)	Elastin degradation is regulated by the membrane-associated matrix metalloproteinase MMP14 (Xiong et al. 2009) and associated with aneurisms.
			R-HSA-2514823 (Reactome)	Fibrillin-1, the major structural component of microfibrils (Kielty et al. 2005), can be degraded by neutrophil elastase (ELANE) (Kielty et al. 1994).
			R-HSA-2514831 (Reactome)	Fibrillin-1 is the major structural component of microfibrils (Kielty et al. 2005). It can be degraded by the membrane-associated MMP14 (Ashworth et al. 1999).
			R-HSA-2533874 (Reactome)	Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Laminin-511 (alpha-5 beta-1gamma-1) is a major structural component of many basement membranes (BMs) including the BM that separates the epidermis from the dermis (Määttä et al. 2001). MMP14 (MT1-MMP) has been shown to cleave the alpha chain of laminin-511, promoting tumor cell migration (Bair et al. 2005). Loss of laminin-511 is a likely contributor to age-related hair loss (Pouliot et al. 2002).
			R-HSA-2533944 (Reactome)	MMP10 can degrade fibronectin (Nicholson et al. 1989).
			R-HSA-2533950 (Reactome)	MMP14 (MT1-MMP) can degrade fibronectin (Shi & Sottile 2011). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) and suggest that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004).
			R-HSA-2533965 (Reactome)	Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
			R-HSA-2533970 (Reactome)	Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
			R-HSA-2534160 (Reactome)	The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. For example, HS-bound FGF was released from cultured cells by treatments with MMP3, rat MMP13, and plasmin (Whitelock et al. 1996). The core protein of HSPG2 can be cleaved by cathepsin S (Liuzzo et al. 1999).
			R-HSA-2534206 (Reactome)	E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.
			R-HSA-2534240 (Reactome)	HSPG2 protein (perlecan) consists of a core protein of molecular weight 470 kDa with three long glycosaminoglycan (GAG) chains attached, each approximately 70-100 kDa. The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. MMP14 and MMP15 (MT1-MMP and MT2-MMP) can degrade HSPG2 (d'Ortho et al. 1997).
			R-HSA-2534248 (Reactome)	DCN consists of a core protein of ?40 kDa attached to a single chondroitin or dermatan sulfate glycosaminoglycan (GAG) chain. It interacts with collagen types I, II (Vogel et al. 1984), III (Witos et al. 2011), VI (Bidanset et al. 1992) and XIV (Ehnis et al. 1997). DCN acts as a sink for all three isoforms of TGF-Beta, binding them while already bound to collagen (Markmann et al. 2000). Degradation of DCN by matrix metalloproteinases MMP2, 3 or 7 results in the release of TGF-beta (Imai et al. 1997). In addition, DCN binds to EGFR (Iozzo et al. 1999) causing prolonged down-regulation of EGFR-mediated mobilization of intracellular calcium (Csordás et al. 2000).
			R-HSA-2534260 (Reactome)	E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment termed CTF3.
			R-HSA-3785684 (Reactome)	Plasma fibronectin (FN1) is degraded by cathepsin G (CTSG) into a characteristic pattern of gelatin-binding peptides of M, = 64000, 40000, and 30000 (Vartio et al. 1981, Vartio 1982). CTSG is activated by UV exposure and can activate matrix metalloproteinases MMP1 and MMP2, but increased levels of MMP activity did not correlate with increased FN degradation in normal human fibroblasts (NHFs) following exposure to UVB (50 mJ/cm2) irradiation, while addtion of CTSG inhibitor decreased FN degradation, suggesting that CTSG is directly responsible for FN1 degradation (Son et al. 2009).
			R-HSA-3788061 (Reactome)	ADAM8 can cleave fibronectin in human cartilage extracts at Ala271/Val272, within a linker region between the fifth and sixth type I domains, producing  ?30-kd and ?50–85-kd fragments with distinctive neoepitopes VRAA271 and 272VYQP that are associated with osteoarthritis (Zack et al. 2006, 2009).
			R-HSA-3788075 (Reactome)	Brevican, a member of the lectican family, is one of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM. Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000). The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010).
			R-HSA-3791149 (Reactome)	Brevican, a member of the lectican family, is one of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM. Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000). The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican (MMP-1, -2, -3, -7, -8, -10, -13 and -19) preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010).
			R-HSA-3791155 (Reactome)	Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Keratinocytes of the skin secrete numerous laminin isoforms, including laminin-511 and laminin-332. Laminin-332 undergoes extensive proteolysis following secretion, which is essential for laminin-332 integration into the BM (Rousselle & Beck 2013). The 200 kDa alpha-3 subunit of laminin-332 is cleaved between the LG3-LG4 subdomains to generate a 165 kDa product. The 160 kDa gamma-2 subunit is cleaved at its N-terminus to produce a 105 kDa protein (Marinkovich et al. 1992). Tissue remodeling may lead to further proteolysis of the 105 kDa subunit within the N-terminus giving rise to a 80 kDa protein (Gianelli et al. 1997, Koshikawa et al. 2005). The resulting N-terminal fragment has EGF-like properties and may activate the EGF receptor, inducing cell migration (Schenk et al. 2003). In much of the early literature it is not clear which subunit of the laminin trimer was cleaved, but in vitro studies have revealed specific enzymes involved in the processing of laminin-332 including MMP2, MMP14 (MT1-MMP), and the C-proteinase family of enzymes, especially bone morphogenic protein 1 (BMP1) and mammalian tolloid (mTLD), isoforms 1 and 3 respectively of UniProt P13497 BMP1 (Sugawara et al. 2008, Rousselle & Beck 2013). The beta-3 and gamma-2 chains of laminin-322 are degraded by matrix metalloproteinase 14 (MMP14, MT1-MMP, Udayakumar et al. 2003, Koshikawa et al. 2000, 2005, Pirilä et al. 2003).
			R-HSA-3791295 (Reactome)	Aggrecan (large aggregating proteoglycan, chondroitin sulfate proteoglycan 1) is a major structural component of cartilage, particularly articular cartilage. The core protein has over 100 chains of chondroitin sulphate and keratan sulphate giving a MWt of about 250 kDa. The core protein has 2 N-terminal globular domains G1 and G2 and a C-terminal globular G3 domain. G2 and G3 are separated by a region heavily modified with negatively charged glycosaminoglycans (GAGs). The two main modifier moieties keratan sulfate (KS) and chondroitin sulfate (CS) are arranged into two CS regions and a KS-rich region. The 15-kDa interglobular linker (IGD) between the N-terminal G1 and G2 domains is particularly susceptible to proteolysis (Caterson et al. 2000). Degradation in this region is associated with the development of osteoarthritis (Troeberg & Nagase 2012). Members of the ADAM (A Disintegrin And Metalloprotease) protein family are believed to be largely responsible for this cleavage (East et al. 2007, Huang & Wu 2008). The majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala393 (numbering used here refers to the UniProt sequence, these residues often desgnated Glu373-Ala374 in literature) in the IGD (Sandy et al. 1992). Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn360-Phe361 bond (numbering used here refers to the UniProt sequence, these residues often desgnated Asn341-Phe342 in literature). (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as other sites towards the C-terminus.
			R-HSA-3791319 (Reactome)	Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
			R-HSA-3814820 (Reactome)	Endorepellin is the 85-kDa C-terminal domain V of HSPG2 (perlecan). It consists of a series of laminin-like globular (LG) domains interconnected by short epidermal growth factor-like repeats (Hohenester & Engel 2002). Endorepellin has angiostatic activity (Mongiat et al. 2003) which is primarily localised in the LG3 domain (Bix et al. 2004). Bone morphogenetic protein 1 (BMP1), its isoform mammalian Tolloid (mTLD), mammalian Tolloid-like-1 and -2 (TLL1, TLL2) (Gonzalez et al. 2005) and cathepsin-L1 (Cailhier et al. 2008) can liberate LG3 by cleaving endorepellin between Asn4196 and Asp4197.
			R-HSA-3827958 (Reactome)	E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.
			R-HSA-3828025 (Reactome)	MMP14 (MT1-MMP) is able to degrade decorin in keratocytes during bFGF-induced corneal neovascularization.
			R-HSA-4086205 (Reactome)	OPN is a substrate for MMP3 and MMP7. Three cleavage sites were identified, Gly166-Leu167, Ala201-Tyr202 (MMP-3 only), and Asp210-Leu211. The resulting OPN fragments facilitate adhesion and migration in vitro through activation of beta1-containing integrins (Agnihotri et al. 2001). OPN has also been shown to be a substrate for liver transglutaminase and plasma transglutaminase factor IIIa, resulting in protein crosslinking (Prince et al. 1991), enhanced cell adhesion, spreading, focal contact formation and migration
			R-HSA-4224014 (Reactome)	E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions cross-link the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.
	SPP1(17-?)	Arrow	R-HSA-4086205 (Reactome)
	SPP1(?-314)	Arrow	R-HSA-4086205 (Reactome)
SPP1			R-HSA-4086205 (Reactome)