BioPAX pathway converted from "HSPG2 (perlecan) degradation by MMP13, CTSS" in the Reactome database. LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Degradation of perlecan by MMP13, CTSS HSPG2 (perlecan) degradation by MMP13, CTSS 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). Authored: Jupe, S, 2012-08-08 Reviewed: Ricard-Blum, Sylvie, 2013-08-13 Edited: Jupe, S, 2013-08-13 HSPG2 HSPG2(22-4391) Perlecan Basement membrane-specific heparan sulfate proteoglycan core protein Reactome DB_ID: 1011570 extracellular region GENE ONTOLOGY GO:0005576 UniProt:P98160 HSPG2 HSPG2 FUNCTION Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development.FUNCTION Endorepellin in an anti-angiogenic and anti-tumor peptide that inhibits endothelial cell migration, collagen-induced endothelial tube morphogenesis and blood vessel growth in the chorioallantoic membrane. Blocks endothelial cell adhesion to fibronectin and type I collagen. Anti-tumor agent in neovascularization. Interaction with its ligand, integrin alpha2/beta1, is required for the anti-angiogenic properties. Evokes a reduction in phosphorylation of receptor tyrosine kinases via alpha2/beta1 integrin-mediated activation of the tyrosine phosphatase, PTPN6.FUNCTION The LG3 peptide has anti-angiogenic properties that require binding of calcium ions for full activity.SUBUNIT Purified perlecan has a strong tendency to aggregate in dimers or stellate structures. It interacts with other basement membrane components such as laminin, prolargin and collagen type IV. Interacts with COL13A1, FGFBP1 and VWA1. Interacts (via C-terminus) with ECM1 (via C-terminus).TISSUE SPECIFICITY Found in the basement membranes.PTM Proteolytic processing produces the C-terminal angiogenic peptide, endorepellin. This peptide can be further processed to produce the LG3 peptide.PTM N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. Perlecan contains three heparan sulfate chains. The LG3 peptide contains at least three and up to five potential O-glycosylation sites but no N-glycosylation.MISCELLANEOUS The LG3 peptide has been found in the urine of patients with end-stage renal disease and in the amniotic fluid of pregnant women with premature rupture of fetal membranes. Homo sapiens NCBI Taxonomy 9606 UniProt P98160 22 EQUAL 4391 EQUAL Reactome Database ID Release 82 1011570 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1011570 Reactome R-HSA-1011570 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1011570.1 Reactome http://www.reactome.org HSPG2(22-?) HSPG2 N-term fragment Perlecan N-term fragment Reactome DB_ID: 2534251 22 EQUAL -1 EQUAL Reactome Database ID Release 82 2534251 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2534251 Reactome R-HSA-2534251 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2534251.2 HSPG2(?-4391) HSPG2 C-term fragment Perlecan C-term fragment Reactome DB_ID: 2534246 -1 EQUAL 4391 EQUAL Reactome Database ID Release 82 2534246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2534246 Reactome R-HSA-2534246 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2534246.1 ACTIVATION Converted from EntitySet in Reactome MMP13, CTSS MMP13, Cathepsin S Reactome DB_ID: 2534222 MMP13 Collagenase 3 MMP13_HUMAN Reactome DB_ID: 1442483 UniProt:P45452 MMP13 MMP13 FUNCTION Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CCN2. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CCN2. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion.ACTIVITY REGULATION Inhibited by TIMP1, TIMP2 and TIMP3. Inhibited by acetohydroxamic acid and other zinc chelators.SUBUNIT Monomer. Interacts with TIMP1, TIMP2 and TIMP3. Binds (via the C-terminal region) to collagen.TISSUE SPECIFICITY Detected in fetal cartilage and calvaria, in chondrocytes of hypertrophic cartilage in vertebrae and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. Detected in chondrocytes from in joint cartilage that have been treated with TNF and IL1B, but not in untreated chondrocytes. Detected in T lymphocytes. Detected in breast carcinoma tissue.INDUCTION Up-regulated by TNF and IL1B.DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme (By similarity).DOMAIN The C-terminal region binds to collagen.PTM The proenzyme is activated by removal of the propeptide; this cleavage can be effected by other matrix metalloproteinases, such as MMP2, MMP3 and MMP14 and may involve several cleavage steps. Cleavage can also be autocatalytic, after partial maturation by another protease or after treatment with 4-aminophenylmercuric acetate (APMA) (in vitro).PTM N-glycosylated.PTM Tyrosine phosphorylated by PKDCC/VLK.SIMILARITY Belongs to the peptidase M10A family. UniProt P45452 104 EQUAL 471 EQUAL Reactome Database ID Release 82 1442483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1442483 Reactome R-HSA-1442483 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1442483.1 CTSS Cathepsin S CATS_HUMAN Reactome DB_ID: 6801535 UniProt:P25774 CTSS CTSS FUNCTION Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules and MHC class II antigen presentation (PubMed:30612035). The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L.SUBUNIT Monomer.SIMILARITY Belongs to the peptidase C1 family. UniProt P25774 115 EQUAL 331 EQUAL Reactome Database ID Release 82 6801535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6801535 Reactome R-HSA-6801535 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6801535.1 Reactome Database ID Release 82 2534222 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2534222 Reactome R-HSA-2534222 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2534222.2 GENE ONTOLOGY GO:0004252 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 2534167 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2534167 Reactome Database ID Release 82 2534160 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2534160 Reactome R-HSA-2534160 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2534160.1 8626565 Pubmed 1996 The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases Whitelock, JM Murdoch, AD Iozzo, RV Underwood, PA J Biol Chem 271:10079-86 10390548 Pubmed 1999 Inflammatory mediators regulate cathepsin S in macrophages and microglia: A role in attenuating heparan sulfate interactions Liuzzo, JP Petanceska, SS Moscatelli, D Devi, LA Mol Med 5:320-33