Extracellular matrix organization (Homo sapiens)

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5, 27, 48442212, 4951, 53, 7377572, 20, 37, 45, 72...132913, 14, 5234, 4030, 46, 6747, 50, 58, 641825, 36, 54, 5513, 2421, 23, 26, 76, 788, 413156933, 59, 65, 79377011, 16, 66, 68, 69, 71616319, 35412, 17cytosolLamininswithgamma-1,gamma-3:Nidogens:HSPG2COL9A2 VTN LAMB1 Integrinalpha6beta1,alpha7beta1,alpha1beta1,alpha2beta1,alphaVbeta1:Laminin-111HAPLN1Ca2+ Tenascins C, R, (X,N)LAMA4 LAMC1 3x4Hyp-COL9A1 ITGAX LAMA3 LAMB1 Collagen type I fibril ITGA2B(32-1039) Integrin alpha6beta1LAMA5 DCN ITGB3 ITGA6(24-1130) Laminin-111Ca2+LAMB3 LUM LAMA1 Fibronectin matrix HAIntegrinalpha5beta1:Fibronectin matrixCollagen type IV alpha3.alpha4.alpha5 network TTR LAMC3 LAMB2 LAMB2 ITGB1 Fibronectin matrix Nidogens 1, 2COMP pentamer:COMPinteractorsLAMC1 LAMC3 LAMA5 Collagen type II fibril MATN4 LAMA3 Collagen type VII fibril LAMA1 ITGA6(24-1130) ITGA2 LUM DystroglycanCollagen type VI fibril LAMB2 ADAM19 DSPP(463-1301):Integrin alphaVbeta1ITGB1 VTN:Collagen typeI,IV,VILAMA1 LAMC1 COMP GalHyl-COL9A3 Collagen type IV alpha3.alpha4.alpha5 network ITGA6(24-1130) Mn2+GlcGalHyl-COL9A1 NID1 Collagen type VI network NID2 Collagen type VI network PTPRS ITGB1 ITGA2 Collagen V Collagen type IV alpha1.alpha1.alpha2 network Lamininswithgamma-1,gamma-3:Nidogens:Collagen type IV networkLAMC2 Collagen type I fibril LAMA4 ADAM15 LAMA2 Collagen type III fibril Collagen type IV alpha1.alpha2.alpha5.alpha6 network Integrin alpha2beta1TGFB3 LAMC3 ADAM19 DAG1(30-653) ITGB1 AGRN:Beta amyloidfibrilTGFB1 Collagen IV LAMB1 ITGA7(34-1181) IntegrinsalphaVbeta1,alphaVbeta3,alphaVbeta5,alpha2bbeta3Collagen type I fibril LAMA4 LAMC1 NRXN1Collagen type II fibril LAMC1 3x4Hyp-GalHyl-COL9A3 ITGA1 DSPP(463-1301) Collagen type X fibril LAMB3 ITGA2 MUSK LAMA3 Collagen IV HSPG2(22-4391) Collagen type II fibril MATN1 3x4Hyp-3Hyp-5Hyl-COL9A3 3x4Hyp-3Hyp-5Hyl-COL9A2 Laminin-3323x4Hyp-COL9A2 ITGAV(31-1048) LRP4 3x4Hyp-3Hyp-GlcGalHyl-COL9A2 Tenascins C, R, (X,N):Lecticans3x4Hyp-3Hyp-GlcGalHyl-COL9A1 DDR1 VTN:IntegrinsalphaVbeta1,alphaVbeta3,alphaVbeta5,alpha2bbeta3DMD Laminins withgamma-1,gamma-3:Nidogens1,2ITGA5(42-894) 5Hyl-COL9A3 LAMA3 LAMA5 SLRPs:TGF betaC4S-BGN CSE-BGN 3x4Hyp-5Hyl-COL9A3 LAMA4 SERPINE1LAMC2 ITGA7(34-1181) LAMB2 AGRN(30-2045)Collagen type IfibrilITGA7(34-1181) ITGB6 3x4Hyp-COL9A1 3x4Hyp-GlcGalHyl-COL9A2 IBSPC4S-BGN LAMA1 Laminins withgamma-1, gamma-3ITGA2B(32-1039) ITGB3 LAMB3 Collagen type VII fibril 3x4Hyp-3Hyp-GalHyl-COL9A3 Collagen type I fibril Collagen type XI fibril DAG1(30-653) LAMB2 Collagen type II fibril NID1 Collagen type III fibril GlcGalHyl-COL9A1 5Hyl-COL9A2 LAMA3 COL9A2 ITGB6 ITGB1 DDR1 dimerAggrecan LAMB2 ITGB1 AGRN(30-2045) LAMA2 LAMB1 3Hyp-4Hyp-COL9A3 3Hyp-4Hyp-COL9A3 Collagen type IV alpha1.alpha1.alpha2 network TNXB LAMC2 Collagen IV C6S-BGN ITGA5(42-894) Integrinalpha3beta1,alpha6beta43x4Hyp-GlcGalHyl-COL9A1 DMP1LAMC1 LAMC3 BGN ITGA6(24-1130) IBSP:Collagen type IfibrilCollagen V DDR2 dimerDAG1(30-653) ITGAV(31-1048) LAMA2 ITGB1 5Hyl-COL9A1 LAMC3 3x4Hyp-GalHyl-COL9A3 ITGB1 DMP1 LAMB1 3x4Hyp-GlcGalHyl-COL9A3 Laminin-111:Endostatin dimerLAMC1 ITGA6(24-1130) GalHyl-COL9A3 LAMA2 LAMB2 3x4Hyp-5Hyl-COL9A1 AGRN(30-2045) ADAM12 DCN:Collagen type I,II, III, VI fibrilsCollagen type IV alpha1.alpha2.alpha5.alpha6 network Collagen type III fibril LAMA2 MATN1 LAMC2 Integrinalpha2beta1:Laminin-332LAMC3 LecticansCollagen type VII fibril ITGB3 LAMB3 3x4Hyp-3Hyp-5Hyl-COL9A1 LAMB3 LAMC3 Collagen type X fibril Collagen V LAMA4 Collagen type III fibril PI(3,4)P2 Dystroglycan:AGRN:HSPG23x4Hyp-GlcGalHyl-COL9A3 Collagen types I-V,VIIDDR2 dimer:Collagentype I, II, III, V,X fibrilsITGB3 ITGB4 Collagen V LAMA3 COL9A3 FN1(32-2386)DAG1(30-653) GlcGalHyl-COL9A3 LAMC1 LAMA3 Laminins withalpha-1, -2 or-5:HSPG2(22-4391)Collagen type IVnetworks:Collagentype VII fibrilTNXB Collagen type II fibril DAG1(654-895) LamininsLamininsADAM12,ADAM15,ADAM19LAMA4 DAG1(30-653) ITGB4 Collagen type IV alpha1.alpha1.alpha2 network LAMB1 Collagen type IV alpha1.alpha1.alpha2 network TGFB1 ITGA8(39-1063) ITGB1 LAMA1 5Hyl-COL9A2 TNC:IntegrinalphaVbeta3,alphaVbeta6,alpha2beta1,alpha7beta1,alpha8beta1,alpha9beta1,alphaXbeta1Collagen type III fibril ITGA7(34-1181) LAMC2 DCN LAMC1 Collagen type VIIfibrilHSPG2(22-4391) LAMC1 TTR FN1(32-2386) Collagen type XI fibril SH3PXD2A:PI(3,4)P2:ADAM12,ADAM15,ADAM19LAMA3 FGF2(10-155),Fibronectn matrix,Transthyretintetramer, PDGFAhomodimer, PDGFBhomodimerSH3PXD2A:PI(3,4)P2KS(2),C6S-ACAN LAMA2 ITGB1 Collagen type III fibril Collagen type II fibril NID2 NID2 LAMB2 LAMA3 Collagen types II,IIILAMB1 LAMA3 Collagen type IV alpha1.alpha2.alpha5.alpha6 network Collagen types I,VI, (IX)COMP ITGB1 LAMA1 KS(2)-FMOD AGRN:Laminins withgamma-1LAMA1 ITGB1 GlcGalHyl-COL9A3 LAMA1 LAMA4 KS(2),C4S-ACAN TNR VTN:Collagen typesII,III,VHSPG2(22-4391)GlcGalHyl-COL9A2 KS(2),CSE-ACAN Versican TNC Degradation of theextracellularmatrixTGFB2 ITGAV(31-1048) LAMA2 KS(2),C4S-ACAN LAMA5 BGN:Collagen typesII, IIILAMA1 Collagen IV Tenascins C, R, (X,N):FibronectinmatrixLaminin-211, 221,332, 411, 512, 521Collagen V Fibronectin matrix LAMB2 ITGA3(33-1051) LAMB2 Neurocan LAMC2 Laminins:SulfatideLAMA2 PDGFB (82-190) MATN3 LAMA5 LAMB3 LAMC1 LAMB2 SPARCLAMA5 TGFB3 Integrinalpha6beta1,alpha7beta1,alpha1beta1,alpha2beta1,alphaVbeta1LAMB2 ITGB3 LAMB1 Collagen formationIntegrinalpha6beta1:Laminin-211, 221, 332, 411, 512, 521LAMC1 Collagen types II,III, VDAG1(654-895) Collagen V LAMB3 Collagen type I fibril Integrin alpha7beta1Collagen type IVnetwork:Laminin-1LAMB2 TNC Aggrecan Collagen type IV alpha3.alpha4.alpha5 network Collagen type II fibril HydroxylapatiteCollagentypeIfibril:SPARC:Hydroxylapatitie:Ca2+MATN3 Dystroglycan:Dystrophin:LamininsLAMB1 ITGB1 Collagen type III fibril Collagen type I, II,III, V, X fibrilsLAMB1 AGRN(30-2045) Aggrecan:HA:HAPLN1LAMA4 BGN:Collagen typesI, VI, (IX)LAMA5 LAMB1 VTNCollagen type I fibril TNC Collagen type I fibril LAMB2 LAMC1 3x4Hyp-3Hyp-GlcGalHyl-COL9A1 Laminin networkLAMB1 Laminins-332, 511,521, (211, 221)TNC DDR1 Integrin cellsurfaceinteractionsNCAM1, PTPRSTenascin-C hexamerITGA5(42-894) 3x4Hyp-3Hyp-GlcGalHyl-COL9A2 LAMB1 Integrinalpha3beta1,alpha6beta4:Laminins-332, 511, 521, (211, 221)FGF2(10-155) 3x4Hyp-5Hyl-COL9A3 Laminins withgamma-1Collagen type III fibril ITGA2 LAMA2 LAMA4 ITGAV(31-1048) LAMB2 VTN LAMA2 ITGA2 Versican 3x4Hyp-3Hyp-COL9A1 ITGA7(34-1181) Collagen IVAGRN:Alpha-dystroglycanNTN4 ITGA6(24-1130) COL9A1 ITGAX ITGB1 TNXB Collagen type I fibril GalHyl-COL9A1 Collagen type II fibril 5Hyl-COL9A3 CEACAM6 Beta amyloid fibril Aggrecan COL18A1(1572-11754) CEACAM8 ITGB1 LAMA4 CSE-BGN LAMA5 CSE-BGN DAG1(30-653) LAMA2 ADAM15 Mn2+ 3x4Hyp-5Hyl-COL9A1 3x4Hyp-GalHyl-COL9A2 LAMC2 COL9A3 DCNLaminins withalpha-1, -2 or -5ITGB3 HSPG2:DystroglycanITGA8(39-1063) Integrin alphaVbeta3DDR2 3x4Hyp-3Hyp-COL9A1 3x4Hyp-GlcGalHyl-COL9A1 PDGFA COL9A1 NCAM1 LAMA1 DAG1(654-895) TNR ITGAV(31-1048) DMDAGRN(30-2045) LAMB1 LAMA4 Collagen type IV alpha1.alpha2.alpha5.alpha6 network TGF betaC4S-BGN KS(2),CSE-ACAN Collagen type I fibril DCN LAMA1 GlcGalHyl-COL9A2 LAMA3 DAG1(654-895) SLRPsCollagen type II fibril LAMB1 DDR2 LAMC3 Collagen V TNN LAMB3 3x4Hyp-3Hyp-GalHyl-COL9A2 VTN HSPG2(22-4391) Collagen type I fibre Collagen type I fibril LAMA1 LRP4:MUSKLAMC1 LAMA5 LAMB1 3x4Hyp-3Hyp-GalHyl-COL9A1 LAMB1 NID1 Integrinalpha5beta1:FN1dimerPI(3,4)P2 3x4Hyp-3Hyp-5Hyl-COL9A1 Collagen type I fibril Collagen type I fibril AGRN(30-2045) LAMB1 LAMC3 Integrinalpha7beta1:Laminin-211, 221, 411, 512, 521DSPP(463-1301)Sulfatide TNN LAMC1 3x4Hyp-COL9A3 ITGAV(31-1048) LAMA4 Collagen type III fibril LAMC1 AGRN:LRP4:MUSKAGRN(30-2045) LAMA5 LAMA5 C6S-BGN MUSK LAMA4 COMP interactorsKS(2),C6S-ACAN SPARC LAMA5 NTN4FN1(32-2386) PDGFA ITGB1 ITGB1 ITGB1 LAMC1 3x4Hyp-GalHyl-COL9A1 DAG1(654-895) LAMA2 3x4Hyp-3Hyp-GalHyl-COL9A2 Collagen type III fibril LAMC2 3x4Hyp-GalHyl-COL9A1 LAMA5 Collagen type II fibril CEACAM heterodimerFibronectin matrix LAMB2 3x4Hyp-3Hyp-GlcGalHyl-COL9A3 HSPG2(22-4391) Collagen type I, II,III, IV, V, XIfibrilsLAMA5 Collagen type II fibril TNR LAMA4 Collagen type I fibril LAMA1 NTN4:Laminins withgamma-1, gamma-3Laminin-111LAMC2 LAMA3 LAMA2 DDR1 dimer:Collagentype I, II, III,IV, V, XI fibrilsC6S-BGN LAMB1 3x4Hyp-GlcGalHyl-COL9A2 NRXN1 COMP pentamer3x4Hyp-COL9A2 3x4Hyp-3Hyp-5Hyl-COL9A3 LAMA5 AggrecanCollagen IV LAMA2 Beta amyloid fibrilHydroxylapatite Brevican Endostatin dimerLAMC2 SERPINE1 PDGFB (82-190) SH3PXD2A IntegrinalphaVbeta3,alphaVbeta6,alpha2beta1,alpha7beta1,alpha8beta1,alpha9beta1,alphaXbeta1LAMC3 AGRN:NCAM1, PTPRSBGNNID1 LAMC2 Collagen type VI fibril FN1(32-2386):Collagen types I-V, VIISulfatidePTPRS Collagen type II fibril 3x4Hyp-3Hyp-GalHyl-COL9A1 3x4Hyp-3Hyp-5Hyl-COL9A2 LAMA3 LAMA2 FN1(32-2386) DAG1(30-653)Collagen type II fibril ITGB5 LAMB1 ITGA9 LAMA3 3x4Hyp-GalHyl-COL9A2 NCAM1 LAMB2 Integrin alpha5beta1FN1 dimerADAM12 Collagen IV LAMC2 COL18A1(1572-11754) LAMC1 Elastic fibreformationITGA7(34-1181) LAMA1 LAMA3 LAMA3 Aggrecan ITGB5 LAMB1 Dystroglycan:NRXN1NID2 Collagen type III fibril LAMA1 BGN ASPN Collagen type I fibril HSPG2(22-4391) LAMC1 TGFB2 GalHyl-COL9A1 LAMC1 LAMA2 Collagen V SyndecaninteractionsLRP4 3x4Hyp-3Hyp-GlcGalHyl-COL9A3 3x4Hyp-COL9A3 Brevican LAMB3 MATN4 LAMC2 LAMB1 Collagen type IV alpha3.alpha4.alpha5 network 3x4Hyp-3Hyp-GalHyl-COL9A3 LAMA3 AGRN(30-2045) Vitronectin:Plasminogen activator inhibitor 1LAMA2 CEACAM1 ITGA1 Neurocan LAMC2 5Hyl-COL9A1 LAMB2 HSPG2(22-4391) HSPG2:FGF2(10-155),Fibronectn matrix,Transthyretintetramer, PDGFAhomodimer, PDGFBhomodimerHAPLN1 KS(2)-FMOD Collagen type VII fibril LAMA3 Integrin alphaVbeta1LAMC1 Laminin-332LAMB2 LAMA4 HA ITGB1 ITGAV(31-1048) Collagen type VI fibril ITGA9 TNN SH3PXD2A 3x4Hyp-5Hyl-COL9A2 LAMA2 ITGA3(33-1051) Collagen type VI fibril Collagen type II fibril GalHyl-COL9A2 LAMA2 LAMC1 ITGA2 LAMB3 LAMB1 LAMA1 ASPN LAMA5 Collagen type I, II,III, VI fibrilsLaminin-211, 221,411, 512, 5213x4Hyp-5Hyl-COL9A2 ITGAV(31-1048) ITGAV(31-1048) LAMA5 IBSP Fibronectin matrixCollagen type III fibril 3x4Hyp-3Hyp-COL9A2 LAMC1 FGF2(10-155) AGRN, HSPG2Collagen typeI,IV,VITNC LAMA1 LAMB3 Collagen type I fibre LAMA5 LAMC1 Collagen type VIIfibril:Laminin-332DMP1:IntegrinalphVbeta3LAMA5 LAMB3 LAMB1 LAMA1 VTN LAMA3 LAMC3 GalHyl-COL9A2 ITGAV(31-1048) 3x4Hyp-3Hyp-COL9A2 3228, 604879436, 39, 621, 15, 38, 42, 747910


Description

The extracellular matrix is a component of all mammalian tissues, a network consisting largely of the fibrous proteins collagen, elastin and associated-microfibrils, fibronectin and laminins embedded in a viscoelastic gel of anionic proteoglycan polymers. It performs many functions in addition to its structural role; as a major component of the cellular microenvironment it influences cell behaviours such as proliferation, adhesion and migration, and regulates cell differentiation and death (Hynes 2009).

ECM composition is highly heterogeneous and dynamic, being constantly remodeled (Frantz et al. 2010) and modulated, largely by matrix metalloproteinases (MMPs) and growth factors that bind to the ECM influencing the synthesis, crosslinking and degradation of ECM components (Hynes 2009). ECM remodeling is involved in the regulation of cell differentiation processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. Redundant mechanisms modulate the expression and function of ECM modifying enzymes. Abnormal ECM dynamics can lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer.

Collagen is the most abundant fibrous protein within the ECM constituting up to 30% of total protein in multicellular animals. Collagen provides tensile strength. It associates with elastic fibres, composed of elastin and fibrillin microfibrils, which give tissues the ability to recover after stretching. Other ECM proteins such as fibronectin, laminins, and matricellular proteins participate as connectors or linking proteins (Daley et al. 2008).

Chondroitin sulfate, dermatan sulfate and keratan sulfate proteoglycans are structural components associated with collagen fibrils (Scott & Haigh 1985; Scott & Orford 1981), serving to tether the fibril to the surrounding matrix. Decorin belongs to the small leucine-rich repeat proteoglycan family (SLRPs) which also includes biglycan, fibromodulin, lumican and asporin. All appear to be involved in collagen fibril formation and matrix assembly (Ameye & Young 2002).

ECM proteins such as osteonectin (SPARC), osteopontin and thrombospondins -1 and -2, collectively referred to as matricellular proteins (reviewed in Mosher & Adams 2012) appear to modulate cell-matrix interactions. In general they induce de-adhesion, characterized by disruption of focal adhesions and a reorganization of actin stress fibers (Bornstein 2009). Thrombospondin (TS)-1 and -2 bind MMP2. The resulting complex is endocytosed by the low-density lipoprotein receptor-related protein (LRP), clearing MMP2 from the ECM (Yang et al. 2001).

Osteopontin (SPP1, bone sialoprotein-1) interacts with collagen and fibronectin (Mukherjee et al. 1995). It also contains several cell adhesive domains that interact with integrins and CD44.

Aggrecan is the predominant ECM proteoglycan in cartilage (Hardingham & Fosang 1992). Its relatives include versican, neurocan and brevican (Iozzo 1998). In articular cartilage the major non-fibrous macromolecules are aggrecan, hyaluronan and hyaluronan and proteoglycan link protein 1 (HAPLN1). The high negative charge density of these molecules leads to the binding of large amounts of water (Bruckner 2006). Hyaluronan is bound by several large proteoglycans proteoglycans belonging to the hyalectan family that form high-molecular weight aggregates (Roughley 2006), accounting for the turgid nature of cartilage.

The most significant enzymes in ECM remodeling are the Matrix Metalloproteinase (MMP) and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families (Cawston & Young 2010). Other notable ECM degrading enzymes include plasmin and cathepsin G. Many ECM proteinases are initially present as precursors, activated by proteolytic processing. MMP precursors include an amino prodomain which masks the catalytic Zn-binding motif (Page-McCawet al. 2007). This can be removed by other proteinases, often other MMPs. ECM proteinases can be inactivated by degradation, or blocked by inhibitors. Some of these inhibitors, including alpha2-macroglobulin, alpha1-proteinase inhibitor, and alpha1-chymotrypsin can inhibit a large variety of proteinases (Woessner & Nagase 2000). The tissue inhibitors of metalloproteinases (TIMPs) are potent MMP inhibitors (Brew & Nagase 2010). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 1474244
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Reactome version: 74
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Reactome Author: Jupe, Steve

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  40. Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, Jin R.; ''Structural basis of agrin-LRP4-MuSK signaling.''; PubMed Europe PMC Scholia
  41. Pytela R, Pierschbacher MD, Ginsberg MH, Plow EF, Ruoslahti E.; ''Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors.''; PubMed Europe PMC Scholia
  42. Erickson HP, Carrell NA.; ''Fibronectin in extended and compact conformations. Electron microscopy and sedimentation analysis.''; PubMed Europe PMC Scholia
  43. Cotman SL, Halfter W, Cole GJ.; ''Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain.''; PubMed Europe PMC Scholia
  44. Probstmeier R, Pesheva P.; ''Tenascin-C inhibits beta1 integrin-dependent cell adhesion and neurite outgrowth on fibronectin by a disialoganglioside-mediated signaling mechanism.''; PubMed Europe PMC Scholia
  45. Abram CL, Seals DF, Pass I, Salinsky D, Maurer L, Roth TM, Courtneidge SA.; ''The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells.''; PubMed Europe PMC Scholia
  46. Vogel W, Gish GD, Alves F, Pawson T.; ''The discoidin domain receptor tyrosine kinases are activated by collagen.''; PubMed Europe PMC Scholia
  47. Behrens DT, Villone D, Koch M, Brunner G, Sorokin L, Robenek H, Bruckner-Tuderman L, Bruckner P, Hansen U.; ''The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens.''; PubMed Europe PMC Scholia
  48. Hauser N, Paulsson M, Heinegârd D, Mörgelin M.; ''Interaction of cartilage matrix protein with aggrecan. Increased covalent cross-linking with tissue maturation.''; PubMed Europe PMC Scholia
  49. Grover J, Roughley PJ.; ''The expression of functional link protein in a baculovirus system: analysis of mutants lacking the A, B and B' domains.''; PubMed Europe PMC Scholia
  50. Leitinger B, Kwan AP.; ''The discoidin domain receptor DDR2 is a receptor for type X collagen.''; PubMed Europe PMC Scholia
  51. Brakebusch C, Fässler R.; ''beta 1 integrin function in vivo: adhesion, migration and more.''; PubMed Europe PMC Scholia
  52. Schwarzbauer JE.; ''Identification of the fibronectin sequences required for assembly of a fibrillar matrix.''; PubMed Europe PMC Scholia
  53. Watanabe H, Cheung SC, Itano N, Kimata K, Yamada Y.; ''Identification of hyaluronan-binding domains of aggrecan.''; PubMed Europe PMC Scholia
  54. Frantz C, Stewart KM, Weaver VM.; ''The extracellular matrix at a glance.''; PubMed Europe PMC Scholia
  55. Singh P, Carraher C, Schwarzbauer JE.; ''Assembly of fibronectin extracellular matrix.''; PubMed Europe PMC Scholia
  56. Mann HH, Ozbek S, Engel J, Paulsson M, Wagener R.; ''Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias.''; PubMed Europe PMC Scholia
  57. Tkachenko E, Rhodes JM, Simons M.; ''Syndecans: new kids on the signaling block.''; PubMed Europe PMC Scholia
  58. Ordonez C, Zhai AB, Camacho-Leal P, Demarte L, Fan MM, Stanners CP.; ''GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction.''; PubMed Europe PMC Scholia
  59. Ehnis T, Dieterich W, Bauer M, Kresse H, Schuppan D.; ''Localization of a binding site for the proteoglycan decorin on collagen XIV (undulin).''; PubMed Europe PMC Scholia
  60. Schönherr E, Witsch-Prehm P, Harrach B, Robenek H, Rauterberg J, Kresse H.; ''Interaction of biglycan with type I collagen.''; PubMed Europe PMC Scholia
  61. Arnaout MA, Goodman SL, Xiong JP.; ''Coming to grips with integrin binding to ligands.''; PubMed Europe PMC Scholia
  62. Eapen A, Ramachandran A, George A.; ''Dentin phosphoprotein (DPP) activates integrin-mediated anchorage-dependent signals in undifferentiated mesenchymal cells.''; PubMed Europe PMC Scholia
  63. Talts JF, Andac Z, Göhring W, Brancaccio A, Timpl R.; ''Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins.''; PubMed Europe PMC Scholia
  64. Rosenberg K, Olsson H, Mörgelin M, Heinegård D.; ''Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen.''; PubMed Europe PMC Scholia
  65. Knox S, Merry C, Stringer S, Melrose J, Whitelock J.; ''Not all perlecans are created equal: interactions with fibroblast growth factor (FGF) 2 and FGF receptors.''; PubMed Europe PMC Scholia
  66. Rousselle P, Keene DR, Ruggiero F, Champliaud MF, Rest M, Burgeson RE.; ''Laminin 5 binds the NC-1 domain of type VII collagen.''; PubMed Europe PMC Scholia
  67. Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Goldfarb MP, Glass DJ, Lemke G, Yancopoulos GD.; ''An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors.''; PubMed Europe PMC Scholia
  68. Yokosaki Y, Monis H, Chen J, Sheppard D.; ''Differential effects of the integrins alpha9beta1, alphavbeta3, and alphavbeta6 on cell proliferative responses to tenascin. Roles of the beta subunit extracellular and cytoplasmic domains.''; PubMed Europe PMC Scholia
  69. Schröder AK, Uciechowski P, Fleischer D, Rink L.; ''Crosslinking of CD66B on peripheral blood neutrophils mediates the release of interleukin-8 from intracellular storage.''; PubMed Europe PMC Scholia
  70. Gebb C, Hayman EG, Engvall E, Ruoslahti E.; ''Interaction of vitronectin with collagen.''; PubMed Europe PMC Scholia
  71. Chen FH, Herndon ME, Patel N, Hecht JT, Tuan RS, Lawler J.; ''Interaction of cartilage oligomeric matrix protein/thrombospondin 5 with aggrecan.''; PubMed Europe PMC Scholia
  72. Belkin AM, Stepp MA.; ''Integrins as receptors for laminins.''; PubMed Europe PMC Scholia
  73. Alexopoulou AN, Multhaupt HA, Couchman JR.; ''Syndecans in wound healing, inflammation and vascular biology.''; PubMed Europe PMC Scholia
  74. Wu H, Teng PN, Jayaraman T, Onishi S, Li J, Bannon L, Huang H, Close J, Sfeir C.; ''Dentin matrix protein 1 (DMP1) signals via cell surface integrin.''; PubMed Europe PMC Scholia
  75. Boudreau NJ, Jones PL.; ''Extracellular matrix and integrin signalling: the shape of things to come.''; PubMed Europe PMC Scholia
  76. Farias E, Lu M, Li X, Schnapp LM.; ''Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway.''; PubMed Europe PMC Scholia
  77. Whinna HC, Choi HU, Rosenberg LC, Church FC.; ''Interaction of heparin cofactor II with biglycan and decorin.''; PubMed Europe PMC Scholia
  78. Nishiuchi R, Takagi J, Hayashi M, Ido H, Yagi Y, Sanzen N, Tsuji T, Yamada M, Sekiguchi K.; ''Ligand-binding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactions using recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins.''; PubMed Europe PMC Scholia
  79. Chen CH, Yeh ML, Geyer M, Wang GJ, Huang MH, Heggeness MH, Höök M, Luo ZP.; ''Interactions between collagen IX and biglycan measured by atomic force microscopy.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114873view16:38, 25 January 2021ReactomeTeamReactome version 75
113556view13:07, 2 November 2020DeSlOntology Term : 'integrin mediated cell-cell signaling pathway' added !
113319view11:39, 2 November 2020ReactomeTeamReactome version 74
112530view15:49, 9 October 2020ReactomeTeamReactome version 73
101442view11:31, 1 November 2018ReactomeTeamreactome version 66
100980view21:09, 31 October 2018ReactomeTeamreactome version 65
100516view19:43, 31 October 2018ReactomeTeamreactome version 64
100062view16:27, 31 October 2018ReactomeTeamreactome version 63
99614view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99223view12:44, 31 October 2018ReactomeTeamreactome version 62
93373view11:21, 9 August 2017ReactomeTeamreactome version 61
86458view09:18, 11 July 2016ReactomeTeamreactome version 56
83106view09:59, 18 November 2015ReactomeTeamVersion54
81438view12:58, 21 August 2015ReactomeTeamVersion53
76914view08:18, 17 July 2014ReactomeTeamFixed remaining interactions
76619view11:59, 16 July 2014ReactomeTeamFixed remaining interactions
75950view10:00, 11 June 2014ReactomeTeamRe-fixing comment source
75652view10:55, 10 June 2014ReactomeTeamReactome 48 Update
75007view13:52, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74651view08:42, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
3Hyp-4Hyp-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-5Hyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-5Hyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-5Hyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
5Hyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
5Hyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
5Hyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
ADAM12 ProteinO43184 (Uniprot-TrEMBL)
ADAM12,ADAM15,ADAM19ComplexR-HSA-8941273 (Reactome)
ADAM15 ProteinQ13444 (Uniprot-TrEMBL)
ADAM19 ProteinQ9H013 (Uniprot-TrEMBL)
AGRN(30-2045) ProteinO00468 (Uniprot-TrEMBL)
AGRN(30-2045)ProteinO00468 (Uniprot-TrEMBL)
AGRN, HSPG2ComplexR-HSA-2426293 (Reactome)
AGRN:Alpha-dystroglycanComplexR-HSA-2467717 (Reactome)
AGRN:Beta amyloid fibrilComplexR-HSA-2467662 (Reactome)
AGRN:LRP4:MUSKComplexR-HSA-2467620 (Reactome)
AGRN:Laminins with gamma-1ComplexR-HSA-2467087 (Reactome)
AGRN:NCAM1, PTPRSComplexR-HSA-2467657 (Reactome)
ASPN ProteinQ9BXN1 (Uniprot-TrEMBL)
Aggrecan R-HSA-2318622 (Reactome)
Aggrecan:HA:HAPLN1ComplexR-HSA-2318621 (Reactome)
AggrecanComplexR-HSA-2318622 (Reactome)
BGN ProteinP21810 (Uniprot-TrEMBL)
BGN:Collagen types I, VI, (IX)ComplexR-HSA-2796107 (Reactome)
BGN:Collagen types II, IIIComplexR-HSA-2466258 (Reactome)
BGNComplexR-HSA-2466248 (Reactome)
Beta amyloid fibril R-HSA-976748 (Reactome)
Beta amyloid fibrilR-HSA-976748 (Reactome)
Brevican R-HSA-2681671 (Reactome)
C4S-BGN ProteinP21810 (Uniprot-TrEMBL)
C6S-BGN ProteinP21810 (Uniprot-TrEMBL)
CEACAM heterodimerComplexR-HSA-202716 (Reactome)
CEACAM1 ProteinP13688 (Uniprot-TrEMBL)
CEACAM6 ProteinP40199 (Uniprot-TrEMBL)
CEACAM8 ProteinP31997 (Uniprot-TrEMBL)
COL18A1(1572-11754) ProteinP39060 (Uniprot-TrEMBL)
COL9A1 ProteinP20849 (Uniprot-TrEMBL)
COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
COMP ProteinP49747 (Uniprot-TrEMBL)
COMP interactorsComplexR-HSA-2426282 (Reactome)
COMP pentamer:COMP interactorsComplexR-HSA-2426278 (Reactome)
COMP pentamerComplexR-HSA-2426264 (Reactome)
CSE-BGN ProteinP21810 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Collagen

type I

fibril:SPARC:Hydroxylapatitie:Ca2+
ComplexR-HSA-2672066 (Reactome)
Collagen IV R-HSA-2564668 (Reactome)
Collagen IVComplexR-HSA-2564668 (Reactome)
Collagen V R-HSA-1609685 (Reactome)
Collagen formationPathwayR-HSA-1474290 (Reactome) Collagen is a family of at least 29 structural proteins derived from over 40 human genes (Myllyharju & Kivirikko 2004). It is the main component of connective tissue, and the most abundant protein in mammals making up about 25% to 35% of whole-body protein content. A defining feature of collagens is the formation of trimeric left-handed polyproline II-type helical collagenous regions. The packing within these regions is made possible by the presence of the smallest amino acid, glycine, at every third residue, resulting in a repeating motif Gly-X-Y where X is often proline (Pro) and Y often 4-hydroxyproline (4Hyp). Gly-Pro-Hyp is the most common triplet in collagen (Ramshaw et al. 1998). Collagen peptide chains also have non-collagenous domains, with collagen subclasses having common chain structures. Collagen fibrils are mostly found in fibrous tissues such as tendon, ligament and skin. Other forms of collagen are abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc. In muscle tissue, collagen is a major component of the endomysium, constituting up to 6% of muscle mass. Gelatin, used in food and industry, is collagen that has been irreversibly hydrolyzed. On the basis of their fibre architecture in tissues, the genetically distinct collagens have been divided into subgroups. Group 1 collagens have uninterrupted triple-helical domains of about 300 nm, forming large extracellular fibrils. They are referred to as the fibril-forming collagens, consisting of collagens types I, II, III, V, XI, XXIV and XXVII. Group 2 collagens are types IV and VII, which have extended triple helices (>350 nm) with imperfections in the Gly-X-Y repeat sequences. Group 3 are the short-chain collagens. These have two subgroups. Group 3A have continuous triple-helical domains (type VI, VIII and X). Group 3B have interrupted triple-helical domains, referred to as the fibril-associated collagens with interrupted triple helices (FACIT collagens, Shaw & Olsen 1991). FACITs include collagen IX, XII, XIV, XVI, XIX, XX, XXI, XXII and XXVI plus the transmembrane collagens (XIII, XVII, XXIII and XXV) and the multiple triple helix domains and interruptions (Multiplexin) collagens XV and XVIII (Myllyharju & Kivirikko 2004). The non-collagenous domains of collagens have regulatory functions; several are biologically active when cleaved from the main peptide chain. Fibrillar collagen peptides all have a large triple helical domain (COL1) bordered by N and C terminal extensions, called the N- and C-propeptides, which are cleaved prior to formation of the collagen fibril. The intact form is referred to as a collagen propeptide, not procollagen, which is used to refer to the trimeric triple-helical precursor of collagen before the propeptides are removed. The C-propeptide, also called the NC1 domain, directs chain association during assembly of the procollagen molecule from its three constituent alpha chains (Hulmes 2002).

Fibril forming collagens are the most familiar and best studied subgroup. Collagen fibres are aggregates or bundles of collagen fibrils, which are themselves polymers of tropocollagen complexes, each consisting of three polypeptide chains known as alpha chains. Tropocollagens are considered the subunit of larger collagen structures. They are approximately 300 nm long and 1.5 nm in diameter, with a left-handed triple-helical structure, which becomes twisted into a right-handed coiled-coil 'super helix' in the collagen fibril. Tropocollagens in the extracellular space polymerize spontaneously with regularly staggered ends (Hulmes 2002). In fibrillar collagens the molecules are staggered by about 67 nm, a unit known as D that changes depending upon the hydration state. Each D-period contains slightly more than four collagen molecules so that every D-period repeat of the microfibril has a region containing five molecules in cross-section, called the 'overlap', and a region containing only four molecules, called the 'gap'. The triple-helices are arranged in a hexagonal or quasi-hexagonal array in cross-section, in both the gap and overlap regions (Orgel et al. 2006). Collagen molecules cross-link covalently to each other via lysine and hydroxylysine side chains. These cross-links are unusual, occuring only in collagen and elastin, a related protein.

The macromolecular structures of collagen are diverse. Several group 3 collagens associate with larger collagen fibers, serving as molecular bridges which stabilize the organization of the extracellular matrix. Type IV collagen is arranged in an interlacing network within the dermal-epidermal junction and vascular basement membranes. Type VI collagen forms distinct microfibrils called beaded filaments. Type VII collagen forms anchoring fibrils. Type VIII and X collagens form hexagonal networks. Type XVII collagen is a component of hemidesmosomes where it is complexed wtih alpha6Beta4 integrin, plectin, and laminin-332 (de Pereda et al. 2009). Type XXIX collagen has been recently reported to be a putative epidermal collagen with highest expression in suprabasal layers (Soderhall et al. 2007). Collagen fibrils/aggregates arranged in varying combinations and concentrations in different tissues provide specific tissue properties. In bone, collagen triple helices lie in a parallel, staggered array with 40 nm gaps between the ends of the tropocollagen subunits, which probably serve as nucleation sites for the deposition of crystals of the mineral component, hydroxyapatite (Ca10(PO4)6(OH)2) with some phosphate. Collagen structure affects cell-cell and cell-matrix communication, tissue construction in growth and repair, and is changed in development and disease (Sweeney et al. 2006, Twardowski et al. 2007). A single collagen fibril can be heterogeneous along its axis, with significantly different mechanical properties in the gap and overlap regions, correlating with the different molecular organizations in these regions (Minary-Jolandan & Yu 2009).
Collagen type I,IV,VIComplexR-HSA-2465873 (Reactome)
Collagen type I fibrilR-HSA-1474201 (Reactome)
Collagen type I fibre R-HSA-2214305 (Reactome)
Collagen type I fibril R-HSA-1474201 (Reactome)
Collagen type I, II,

III, IV, V, XI

fibrils
ComplexR-HSA-2465885 (Reactome)
Collagen type I, II, III, V, X fibrilsComplexR-HSA-2465861 (Reactome)
Collagen type I, II, III, VI fibrilsComplexR-HSA-2466225 (Reactome)
Collagen type II fibril R-HSA-1474209 (Reactome)
Collagen type III fibril R-HSA-1474212 (Reactome)
Collagen type IV network:Laminin-1ComplexR-HSA-2426371 (Reactome)
Collagen type IV

networks:Collagen

type VII fibril
ComplexR-HSA-4084523 (Reactome)
Collagen type IV alpha1.alpha1.alpha2 network R-HSA-2214294 (Reactome)
Collagen type IV alpha1.alpha2.alpha5.alpha6 network R-HSA-2564665 (Reactome)
Collagen type IV alpha3.alpha4.alpha5 network R-HSA-2564669 (Reactome)
Collagen type VI fibril R-HSA-1637827 (Reactome)
Collagen type VI network R-HSA-2214296 (Reactome)
Collagen type VII fibril:Laminin-332ComplexR-HSA-2220790 (Reactome)
Collagen type VII fibrilR-HSA-2214333 (Reactome)
Collagen type VII fibril R-HSA-2214333 (Reactome)
Collagen type X fibril R-HSA-2167968 (Reactome)
Collagen type XI fibril R-HSA-2168008 (Reactome)
Collagen types I, VI, (IX)ComplexR-HSA-2466158 (Reactome)
Collagen types I-V, VIIComplexR-HSA-2564686 (Reactome)
Collagen types II, III, VComplexR-HSA-2465902 (Reactome)
Collagen types II, IIIComplexR-HSA-2466171 (Reactome)
DAG1(30-653) ProteinQ14118 (Uniprot-TrEMBL)
DAG1(30-653)ProteinQ14118 (Uniprot-TrEMBL)
DAG1(654-895) ProteinQ14118 (Uniprot-TrEMBL)
DCN ProteinP07585 (Uniprot-TrEMBL)
DCN:Collagen type I, II, III, VI fibrilsComplexR-HSA-2466196 (Reactome)
DCNProteinP07585 (Uniprot-TrEMBL)
DDR1 ProteinQ08345 (Uniprot-TrEMBL)
DDR1 dimer:Collagen

type I, II, III,

IV, V, XI fibrils
ComplexR-HSA-2465848 (Reactome)
DDR1 dimerComplexR-HSA-2327930 (Reactome)
DDR2 ProteinQ16832 (Uniprot-TrEMBL)
DDR2 dimer:Collagen

type I, II, III, V,

X fibrils
ComplexR-HSA-2465856 (Reactome)
DDR2 dimerComplexR-HSA-2327882 (Reactome)
DMD ProteinP11532 (Uniprot-TrEMBL)
DMDProteinP11532 (Uniprot-TrEMBL)
DMP1 ProteinQ13316 (Uniprot-TrEMBL)
DMP1:Integrin alphVbeta3ComplexR-HSA-4086146 (Reactome)
DMP1ProteinQ13316 (Uniprot-TrEMBL)
DSPP(463-1301) ProteinQ9NZW4 (Uniprot-TrEMBL)
DSPP(463-1301):Integrin alphaVbeta1ComplexR-HSA-4086137 (Reactome)
DSPP(463-1301)ProteinQ9NZW4 (Uniprot-TrEMBL)
Degradation of the

extracellular

matrix
PathwayR-HSA-1474228 (Reactome) Matrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003).
Dystroglycan:AGRN:HSPG2ComplexR-HSA-2426244 (Reactome)
Dystroglycan:Dystrophin:LamininsComplexR-HSA-2396153 (Reactome)
Dystroglycan:NRXN1ComplexR-HSA-2426312 (Reactome)
DystroglycanComplexR-HSA-2328140 (Reactome)
Elastic fibre formationPathwayR-HSA-1566948 (Reactome) Elastic fibres (EF) are a major structural constituent of dynamic connective tissues such as large arteries and lung parenchyma, where they provide essential properties of elastic recoil and resilience. EF are composed of a central cross-linked core of elastin, surrounded by a mesh of microfibrils, which are composed largely of fibrillin. In addition to elastin and fibrillin-1, over 30 ancillary proteins are involved in mediating important roles in elastic fibre assembly as well as interactions with the surrounding environment. These include fibulins, elastin microfibril interface located proteins (EMILINs), microfibril-associated glycoproteins (MAGPs) and Latent TGF-beta binding proteins (LTBPs). Fibulin-5 for example, is expressed by vascular smooth muscle cells and plays an essential role in the formation of elastic fibres through mediating interactions between elastin and fibrillin (Yanigasawa et al. 2002, Freeman et al. 2005). In addition, it plays a role in cell adhesion through integrin receptors and has been shown to influence smooth muscle cell proliferation (Yanigasawa et al. 2002, Nakamura et al. 2002). EMILINs are a family of homologous glycoproteins originally identified in extracts of aortas. Found at the elastin-fibrillin interface, early studies showed that antibodies to EMILIN can affect the process of elastic fibre formation (Bressan et al. 1993). EMILIN1 has been shown to bind elastin and fibulin-5 and appears to coordinate their common interaction (Zanetti et al. 2004). MAGPs are found to co-localize with microfibrils. MAGP-1, for example, binds strongly to an N-terminal sequence of fibrillin-1. Other proteins found associated with microfibrils include vitronectin (Dahlback et al. 1990).

Fibrillin is most familiar as a component of elastic fibres but microfibrils with no elastin are found in the ciliary zonules of the eye and invertebrate circulatory systems. The addition of elastin to microfibrils is a vertebrate adaptation to high pulsatile pressures in their closed circulatory systems (Faury et al. 2003). Elastin appears to have emerged after the divergence of jawless vertebrates from other vertebrates (Sage 1982).

Fibrillin-1 is the major structural component of microfibrils. Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. It was first isolated from human brain (Corson et al. 2004).

Fibrillin assembly is not as well defined as elastin assembly. The primary structure of fibrillin is dominated by calcium binding epidermal growth factor like repeats (Kielty et al. 2002). Fibrillin may form dimers or trimers before secretion. However, multimerisation predominantly occurs outside the cell. Formation of fibrils appears to require cell surface structures suggesting an involvement of cell surface receptors. Fibrillin is assembled pericellularly (i.e. on or close to the cell surface) into microfibrillar arrays that undergo time dependent maturation into microfibrils with beaded-string appearance. Transglutaminase forms gamma glutamyl epsilon lysine isopeptide bonds within or between peptide chains. Additionally, intermolecular disulfide bond formation between fibrillins is an important contributor to fibril maturation (Reinhardt et al. 2000).

Models of fibrillin-1 microfibril structure suggest that the N-terminal half of fibrillin-1 is asymmetrically exposed in outer filaments, while the C-terminal half is buried in the interior (Kuo et al. 2007). Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm, all due to mutations in the fibrillin-1 gene FBN1, and congenital contractural arachnodactyly which is caused by mutation of FBN2 (Maslen & Glanville 1993, Davis & Summers 2012).

In vivo assembly of fibrillin requires the presence of extracellular fibronectin fibres (Sabatier et al. 2009). Fibrillins have Arg-Gly-Asp (RGD) sequences that interact with integrins (Pfaff et al. 1996, Sakamoto et al. 1996, Bax et al., 2003, Jovanovic et al. 2008) and heparin-binding domains that interact with a cell-surface heparan sulfate proteoglycan (Tiedemann et al. 2001) possibly a syndecan (Ritty et al. 2003). Fibrillins also have a major role in binding and sequestering growth factors such as TGF beta into the ECM (Neptune et al. 2003). Proteoglycans such as versican (Isogai et al. 2002), biglycan, and decorin (Reinboth et al. 2002) can interact with the microfibrils. They confer specific properties including hydration, impact absorption, molecular sieving, regulation of cellular activities, mediation of growth factor association, and release and transport within the extracellular matrix (Buczek-Thomas et al. 2002). In addition, glycosaminoglycans have been shown to interact with tropoelastin through its lysine side chains (Wu et al. 1999), regulating tropoelastin assembly (Tu & Weiss 2008).

Elastin is synthesized as a 70kDa monomer called tropoelastin, a highly hydrophobic protein composed largely of two types of domains that alternate along the polypeptide chain. Hydrophobic domains are rich in glycine, proline, alanine, leucine and valine. These amino acids occur in characteristic short (3-9 amino acids) tandem repeats, with a flexible and highly dynamic structure (Floquet et al. 2004). Unlike collagen, glycine in elastin is not rigorously positioned every 3 residues. However, glycine is distributed frequently throughout all hydrophobic domains of elastin, and displays a strong preference for inter-glycine spacing of 0-3 residues (Rauscher et al. 2006).

Elastic fibre formation involves the deposition of tropoelastin onto a template of fibrillin rich microfibrils. Recent results suggest that the first step of elastic fiber formation is the organization of small globules of elastin on the cell surface followed by globule aggregation into microfibres (Kozel et al. 2006). An important contribution to the initial stages assembly is thought to be made by the intrinsic ability of the protein to direct its own polymeric organization in a process termed 'coacervation' (Bressan et al. 1986). This self-assembly process appears to be determined by interactions between hydrophobic domains (Bressan et al. 1986, Vrhovski et al. 1997, Bellingham et al. 2003, Cirulis & Keeley 2010) which result in alignment of the cross-linking domains, allowing the stabilization of elastin through the formation of cross-links generated through the oxidative deamination of lysine residues, catalyzed by members of the lysyl oxidase (LOX) family (Reiser et al. 1992, Mithieux & Weiss 2005). The first step in the cross-linking reaction is the oxidative formation of the delta aldehyde, known as alpha aminoadipic semialdehyde or allysine (Partridge 1963). Subsequent reactions that are probably spontaneous lead to the formation of cross-links through dehydrolysinonorleucine and allysine aldol, a trifunctional cross-link dehydromerodesmosine and two tetrafunctional cross-links desmosine and isodesmosine (Lucero & Kagan 2006), which are unique to elastin. These cross-links confer mechanical integrity and high durability. In addition to their role in self-assembly, hydrophobic domains provide elastin with its elastomeric properties, with initial studies suggesting that the elastomeric propereties of elastin are driven through changes in entropic interactions with surrounding water molecules (Hoeve & Flory 1974).

A very specific set of proteases, broadly grouped under the name elastases, is responsible for elastin remodelling (Antonicelli et al. 2007). The matrix metalloproteinases (MMPs) are particularly important in elastin breakdown, with MMP2, 3, 9 and 12 explicitly shown to degrade elastin (Ra & Parks 2007). Nonetheless, elastin typically displays a low turnover rate under normal conditions over a lifetime (Davis 1993).
Endostatin dimerComplexR-HSA-4084521 (Reactome)
FGF2(10-155) ProteinP09038 (Uniprot-TrEMBL)
FGF2(10-155),

Fibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB

homodimer
ComplexR-HSA-2426289 (Reactome)
FN1 dimerComplexR-HSA-266103 (Reactome)
FN1(32-2386) ProteinP02751 (Uniprot-TrEMBL)
FN1(32-2386):Collagen types I-V, VIIComplexR-HSA-2396095 (Reactome)
FN1(32-2386)ProteinP02751 (Uniprot-TrEMBL)
Fibronectin matrix R-HSA-2327729 (Reactome)
Fibronectin matrixR-HSA-2327729 (Reactome)
GalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
GalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
GalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
GlcGalHyl-COL9A1 ProteinP20849 (Uniprot-TrEMBL)
GlcGalHyl-COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
GlcGalHyl-COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
HA R-ALL-2160848 (Reactome)
HAPLN1 ProteinP10915 (Uniprot-TrEMBL)
HAPLN1ProteinP10915 (Uniprot-TrEMBL)
HAR-ALL-2160848 (Reactome)
HSPG2(22-4391) ProteinP98160 (Uniprot-TrEMBL)
HSPG2(22-4391)ProteinP98160 (Uniprot-TrEMBL)
HSPG2:DystroglycanComplexR-HSA-2426324 (Reactome)
HSPG2:FGF2(10-155),

Fibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB

homodimer
ComplexR-HSA-2426668 (Reactome)
Hydroxylapatite MetaboliteCHEBI:52255 (ChEBI)
HydroxylapatiteMetaboliteCHEBI:52255 (ChEBI)
IBSP ProteinP21815 (Uniprot-TrEMBL)
IBSP:Collagen type I fibrilComplexR-HSA-4127482 (Reactome)
IBSPProteinP21815 (Uniprot-TrEMBL)
ITGA1 ProteinP56199 (Uniprot-TrEMBL)
ITGA2 ProteinP17301 (Uniprot-TrEMBL)
ITGA2B(32-1039) ProteinP08514 (Uniprot-TrEMBL)
ITGA3(33-1051) ProteinP26006 (Uniprot-TrEMBL)
ITGA5(42-894) ProteinP08648 (Uniprot-TrEMBL)
ITGA6(24-1130) ProteinP23229 (Uniprot-TrEMBL)
ITGA7(34-1181) ProteinQ13683 (Uniprot-TrEMBL)
ITGA8(39-1063) ProteinP53708 (Uniprot-TrEMBL)
ITGA9 ProteinQ13797 (Uniprot-TrEMBL)
ITGAV(31-1048) ProteinP06756 (Uniprot-TrEMBL)
ITGAX ProteinP20702 (Uniprot-TrEMBL)
ITGB1 ProteinP05556 (Uniprot-TrEMBL)
ITGB3 ProteinP05106 (Uniprot-TrEMBL)
ITGB4 ProteinP16144 (Uniprot-TrEMBL)
ITGB5 ProteinP18084 (Uniprot-TrEMBL)
ITGB6 ProteinP18564 (Uniprot-TrEMBL)
Integrin alpha2beta1:Laminin-332ComplexR-HSA-349628 (Reactome)
Integrin

alpha3beta1,

alpha6beta4:Laminins-332, 511, 521, (211, 221)
ComplexR-HSA-3907294 (Reactome)
Integrin

alpha3beta1,

alpha6beta4
ComplexR-HSA-2426349 (Reactome)
Integrin

alpha5beta1:FN1

dimer
ComplexR-HSA-202708 (Reactome)
Integrin alpha5beta1:Fibronectin matrixComplexR-HSA-2327790 (Reactome)
Integrin

alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,

alphaVbeta1:Laminin-111
ComplexR-HSA-3907290 (Reactome)
Integrin

alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,

alphaVbeta1
ComplexR-HSA-3907291 (Reactome)
Integrin alpha6beta1:Laminin-211, 221, 332, 411, 512, 521ComplexR-HSA-3907287 (Reactome)
Integrin alpha7beta1:Laminin-211, 221, 411, 512, 521ComplexR-HSA-215995 (Reactome)
Integrin

alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,

alphaXbeta1
ComplexR-HSA-2681746 (Reactome)
Integrin alpha2beta1ComplexR-HSA-114561 (Reactome)
Integrin alpha5beta1ComplexR-HSA-202730 (Reactome)
Integrin alpha6beta1ComplexR-HSA-204443 (Reactome)
Integrin alpha7beta1ComplexR-HSA-215998 (Reactome)
Integrin alphaVbeta1ComplexR-HSA-216015 (Reactome)
Integrin alphaVbeta3ComplexR-HSA-210216 (Reactome)
Integrin cell

surface

interactions
PathwayR-HSA-216083 (Reactome) The extracellular matrix (ECM) is a network of macro-molecules that underlies all epithelia and endothelia and that surrounds all connective tissue cells. This matrix provides the mechanical strength and also influences the behavior and differentiation state of cells in contact with it. The ECM are diverse in composition, but they generally comprise a mixture of fibrillar proteins, polysaccharides synthesized, secreted and organized by neighboring cells. Collagens, fibronectin, and laminins are the principal components involved in cell matrix interactions; other components, such as vitronectin, thrombospondin, and osteopontin, although less abundant, are also important adhesive molecules.
Integrins are the receptors that mediate cell adhesion to ECM. Integrins consists of one alpha and one beta subunit forming a noncovalently bound heterodimer. 18 alpha and 8 beta subunits have been identified in humans that combine to form 24 different receptors.
The integrin dimers can be broadly divided into three families consisting of the beta1, beta2/beta7, and beta3/alphaV integrins. beta1 associates with 12 alpha-subunits and can be further divided into RGD-, collagen-, or laminin binding and the related alpha4/alpha9 integrins that recognise both matrix and vascular ligands. beta2/beta7 integrins are restricted to leukocytes and mediate cell-cell rather than cell-matrix interactions, although some recognize fibrinogen. The beta3/alphaV family members are all RGD receptors and comprise aIIbb3, an important receptor on platelets, and the remaining b-subunits, which all associate with alphaV. It is the collagen receptors and leukocyte-specific integrins that contain alpha A-domains.
Integrins

alphaVbeta1, alphaVbeta3, alphaVbeta5,

alpha2bbeta3
ComplexR-HSA-2466235 (Reactome)
KS(2),C4S-ACAN ProteinP16112 (Uniprot-TrEMBL)
KS(2),C6S-ACAN ProteinP16112 (Uniprot-TrEMBL)
KS(2),CSE-ACAN ProteinP16112 (Uniprot-TrEMBL)
KS(2)-FMOD ProteinQ06828 (Uniprot-TrEMBL)
LAMA1 ProteinP25391 (Uniprot-TrEMBL)
LAMA2 ProteinP24043 (Uniprot-TrEMBL)
LAMA3 ProteinQ16787 (Uniprot-TrEMBL)
LAMA4 ProteinQ16363 (Uniprot-TrEMBL)
LAMA5 ProteinO15230 (Uniprot-TrEMBL)
LAMB1 ProteinP07942 (Uniprot-TrEMBL)
LAMB2 ProteinP55268 (Uniprot-TrEMBL)
LAMB3 ProteinQ13751 (Uniprot-TrEMBL)
LAMC1 ProteinP11047 (Uniprot-TrEMBL)
LAMC2 ProteinQ13753 (Uniprot-TrEMBL)
LAMC3 ProteinQ9Y6N6 (Uniprot-TrEMBL)
LRP4 ProteinO75096 (Uniprot-TrEMBL)
LRP4:MUSKComplexR-HSA-2467599 (Reactome)
LUM ProteinP51884 (Uniprot-TrEMBL)
Laminin networkR-HSA-2426622 (Reactome)
Laminin-111:Endostatin dimerComplexR-HSA-4084617 (Reactome)
Laminin-111ComplexR-HSA-215989 (Reactome)
Laminin-211, 221, 332, 411, 512, 521ComplexR-HSA-3907306 (Reactome)
Laminin-211, 221, 411, 512, 521ComplexR-HSA-3907299 (Reactome)
Laminin-332ComplexR-HSA-216001 (Reactome)
Laminins

with gamma-1,

gamma-3:Nidogens:Collagen type IV network
ComplexR-HSA-2426607 (Reactome)
Laminins

with gamma-1,

gamma-3:Nidogens:HSPG2
ComplexR-HSA-2426291 (Reactome)
Laminins with

alpha-1, -2 or

-5:HSPG2(22-4391)
ComplexR-HSA-4084512 (Reactome)
Laminins with alpha-1, -2 or -5ComplexR-HSA-4084530 (Reactome)
Laminins with

gamma-1, gamma-3:Nidogens

1,2
ComplexR-HSA-2426517 (Reactome)
Laminins with gamma-1, gamma-3ComplexR-HSA-2426529 (Reactome)
Laminins with gamma-1ComplexR-HSA-2467086 (Reactome)
Laminins-332, 511, 521, (211, 221)ComplexR-HSA-2426352 (Reactome)
Laminins:SulfatideComplexR-HSA-2465849 (Reactome)
LamininsComplexR-HSA-2328121 (Reactome)
LamininsComplexR-HSA-2426651 (Reactome)
LecticansComplexR-HSA-2681687 (Reactome)
MATN1 ProteinP21941 (Uniprot-TrEMBL)
MATN3 ProteinO15232 (Uniprot-TrEMBL)
MATN4 ProteinO95460 (Uniprot-TrEMBL)
MUSK ProteinO15146 (Uniprot-TrEMBL)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
Mn2+MetaboliteCHEBI:29035 (ChEBI)
NCAM1 ProteinP13591 (Uniprot-TrEMBL)
NCAM1, PTPRSComplexR-HSA-2467656 (Reactome)
NID1 ProteinP14543 (Uniprot-TrEMBL)
NID2 ProteinQ14112 (Uniprot-TrEMBL)
NRXN1 ProteinQ9ULB1 (Uniprot-TrEMBL)
NRXN1ProteinQ9ULB1 (Uniprot-TrEMBL)
NTN4 ProteinQ9HB63 (Uniprot-TrEMBL)
NTN4:Laminins with gamma-1, gamma-3ComplexR-HSA-2426487 (Reactome)
NTN4ProteinQ9HB63 (Uniprot-TrEMBL)
Neurocan R-HSA-2681685 (Reactome)
Nidogens 1, 2ComplexR-HSA-388771 (Reactome)
PDGFA ProteinP04085 (Uniprot-TrEMBL)
PDGFB (82-190) ProteinP01127 (Uniprot-TrEMBL)
PI(3,4)P2 MetaboliteCHEBI:16152 (ChEBI)
PTPRS ProteinQ13332 (Uniprot-TrEMBL)
SERPINE1 ProteinP05121 (Uniprot-TrEMBL)
SERPINE1ProteinP05121 (Uniprot-TrEMBL)
SH3PXD2A ProteinQ5TCZ1 (Uniprot-TrEMBL)
SH3PXD2A:PI(3,4)P2:ADAM12,ADAM15,ADAM19ComplexR-HSA-8941274 (Reactome)
SH3PXD2A:PI(3,4)P2ComplexR-HSA-8941238 (Reactome)
SLRPs:TGF betaComplexR-HSA-2467308 (Reactome)
SLRPsComplexR-HSA-2466213 (Reactome)
SPARC ProteinP09486 (Uniprot-TrEMBL)
SPARCProteinP09486 (Uniprot-TrEMBL)
Sulfatide MetaboliteCHEBI:18318 (ChEBI)
SulfatideMetaboliteCHEBI:18318 (ChEBI)
Syndecan interactionsPathwayR-HSA-3000170 (Reactome) Syndecans are type I transmembrane proteins, with an N-terminal ectodomain that contains several consensus sequences for glycosaminoglycan (GAG) attachment and a short C-terminal cytoplasmic domain. Syndecan-1 and -3 GAG attachment sites occur in two distinct clusters, one near the N-terminus and the other near the membrane-attachment site, separated by a proline and threonine-rich 'spacer'. Syndecan ectodomain sequences are poorly conserved in the family and between species, but the transmembrane and cytoplasmic domains are highly conserved. Syndecan-1 and -3 form a subfamily. Syndecan core proteins form dimers (Choi et al. 2007) and at least syndecan-3 and -4 form oligomers (Asundi & Carey 1995, Shin et al. 2012). Syndecan-1 is the major syndecan of epithelial cells including vascular endothelium. Syndecan-2 is present mostly in mesenchymal, neuronal and smooth muscle cells. Syndecan-3 is the major syndecan of the nervous system, while syndecan-4 is ubiquitously expressed but at lower levels than the other syndecans (refs in Alexopoulou et al. 2007). The core syndecan protein has three to five heparan sulfate or chondroitin sulfate chains, which interact with a variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin, collagen, vitronectin and several integrins. Syndecans may act as integrin coreceptors. Interactions between fibronectin and syndecans are modulated by tenascin-C. Syndecans bind a wide variety of soluble and insoluble ligands, inckluding extracellular matrix components, cell adhesion molecules, growth factors, cytokines, and proteinases. As the cleaved ectodomains of syndecans retain the ability to bind ligands, ectodomain shedding is a mechanism for releasing soluble effectors that may compete for ligands with their cell-bound counterparts (Kainulainen et al. 1998). Shed ectodomains are found in inflammatory fluids (Subramanian et al. 1997) and may induce the proliferation of cancer cells (Maeda et al. 2004).
TGF betaComplexR-HSA-114657 (Reactome)
TGFB1 ProteinP01137 (Uniprot-TrEMBL)
TGFB2 ProteinP61812 (Uniprot-TrEMBL)
TGFB3 ProteinP10600 (Uniprot-TrEMBL)
TNC ProteinP24821 (Uniprot-TrEMBL)
TNC:Integrin

alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,

alphaXbeta1
ComplexR-HSA-2681748 (Reactome)
TNN ProteinQ9UQP3 (Uniprot-TrEMBL)
TNR ProteinQ92752 (Uniprot-TrEMBL)
TNXB ProteinP22105 (Uniprot-TrEMBL)
TTR ProteinP02766 (Uniprot-TrEMBL)
Tenascin-C hexamerComplexR-HSA-216010 (Reactome)
Tenascins C, R, (X,

N):Fibronectin

matrix
ComplexR-HSA-2681744 (Reactome)
Tenascins C, R, (X, N):LecticansComplexR-HSA-2681670 (Reactome)
Tenascins C, R, (X, N)ComplexR-HSA-2672035 (Reactome)
VTN ProteinP04004 (Uniprot-TrEMBL)
VTN:Collagen type I,IV,VIComplexR-HSA-2465898 (Reactome)
VTN:Collagen types II,III,VComplexR-HSA-2465830 (Reactome)
VTN:Integrins

alphaVbeta1, alphaVbeta3, alphaVbeta5,

alpha2bbeta3
ComplexR-HSA-2466116 (Reactome)
VTNProteinP04004 (Uniprot-TrEMBL)
Versican R-HSA-2681688 (Reactome)
Vitronectin:Plasminogen activator inhibitor 1ComplexR-HSA-2466242 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM12,ADAM15,ADAM19R-HSA-8941234 (Reactome)
AGRN(30-2045)R-HSA-2396124 (Reactome)
AGRN(30-2045)R-HSA-2467633 (Reactome)
AGRN(30-2045)R-HSA-2467659 (Reactome)
AGRN(30-2045)R-HSA-2467665 (Reactome)
AGRN(30-2045)R-HSA-2467716 (Reactome)
AGRN, HSPG2R-HSA-2396113 (Reactome)
AGRN:Alpha-dystroglycanArrowR-HSA-2467716 (Reactome)
AGRN:Beta amyloid fibrilArrowR-HSA-2467665 (Reactome)
AGRN:LRP4:MUSKArrowR-HSA-2467633 (Reactome)
AGRN:Laminins with gamma-1ArrowR-HSA-2396124 (Reactome)
AGRN:NCAM1, PTPRSArrowR-HSA-2467659 (Reactome)
Aggrecan:HA:HAPLN1ArrowR-HSA-2318623 (Reactome)
AggrecanR-HSA-2318623 (Reactome)
BGN:Collagen types I, VI, (IX)ArrowR-HSA-2466106 (Reactome)
BGN:Collagen types II, IIIArrowR-HSA-2466238 (Reactome)
BGNR-HSA-2466106 (Reactome)
BGNR-HSA-2466238 (Reactome)
Beta amyloid fibrilR-HSA-2467665 (Reactome)
CEACAM heterodimerArrowR-HSA-202723 (Reactome)
COMP interactorsR-HSA-2424252 (Reactome)
COMP pentamer:COMP interactorsArrowR-HSA-2424252 (Reactome)
COMP pentamerR-HSA-2424252 (Reactome)
Ca2+R-HSA-2424243 (Reactome)
Collagen

type I

fibril:SPARC:Hydroxylapatitie:Ca2+
ArrowR-HSA-2424243 (Reactome)
Collagen IVR-HSA-2328145 (Reactome)
Collagen IVR-HSA-2426450 (Reactome)
Collagen IVR-HSA-4084501 (Reactome)
Collagen type I,IV,VIR-HSA-2465883 (Reactome)
Collagen type I fibrilR-HSA-2424243 (Reactome)
Collagen type I fibrilR-HSA-4086204 (Reactome)
Collagen type I, II,

III, IV, V, XI

fibrils
R-HSA-2327738 (Reactome)
Collagen type I, II, III, V, X fibrilsR-HSA-2465890 (Reactome)
Collagen type I, II, III, VI fibrilsR-HSA-2327909 (Reactome)
Collagen type IV network:Laminin-1ArrowR-HSA-2328145 (Reactome)
Collagen type IV

networks:Collagen

type VII fibril
ArrowR-HSA-4084501 (Reactome)
Collagen type VII fibril:Laminin-332ArrowR-HSA-3787997 (Reactome)
Collagen type VII fibrilR-HSA-3787997 (Reactome)
Collagen type VII fibrilR-HSA-4084501 (Reactome)
Collagen types I, VI, (IX)R-HSA-2466106 (Reactome)
Collagen types I-V, VIIR-HSA-2327733 (Reactome)
Collagen types II, III, VR-HSA-2396370 (Reactome)
Collagen types II, IIIR-HSA-2466238 (Reactome)
DAG1(30-653)R-HSA-2467716 (Reactome)
DCN:Collagen type I, II, III, VI fibrilsArrowR-HSA-2327909 (Reactome)
DCNR-HSA-2327909 (Reactome)
DDR1 dimer:Collagen

type I, II, III,

IV, V, XI fibrils
ArrowR-HSA-2327738 (Reactome)
DDR1 dimerR-HSA-2327738 (Reactome)
DDR2 dimer:Collagen

type I, II, III, V,

X fibrils
ArrowR-HSA-2465890 (Reactome)
DDR2 dimerR-HSA-2465890 (Reactome)
DMDR-HSA-2328129 (Reactome)
DMP1:Integrin alphVbeta3ArrowR-HSA-4086200 (Reactome)
DMP1R-HSA-4086200 (Reactome)
DSPP(463-1301):Integrin alphaVbeta1ArrowR-HSA-4086132 (Reactome)
DSPP(463-1301)R-HSA-4086132 (Reactome)
Dystroglycan:AGRN:HSPG2ArrowR-HSA-2396113 (Reactome)
Dystroglycan:Dystrophin:LamininsArrowR-HSA-2328129 (Reactome)
Dystroglycan:NRXN1ArrowR-HSA-2426263 (Reactome)
DystroglycanR-HSA-2328129 (Reactome)
DystroglycanR-HSA-2396113 (Reactome)
DystroglycanR-HSA-2396395 (Reactome)
DystroglycanR-HSA-2426263 (Reactome)
Endostatin dimerR-HSA-4084507 (Reactome)
FGF2(10-155),

Fibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB

homodimer
R-HSA-2396337 (Reactome)
FN1 dimerArrowR-HSA-2545196 (Reactome)
FN1 dimerR-HSA-202723 (Reactome)
FN1(32-2386):Collagen types I-V, VIIArrowR-HSA-2327733 (Reactome)
FN1(32-2386)R-HSA-2327733 (Reactome)
FN1(32-2386)R-HSA-2327746 (Reactome)
FN1(32-2386)R-HSA-2545196 (Reactome)
Fibronectin matrixR-HSA-2681681 (Reactome)
HAPLN1R-HSA-2318623 (Reactome)
HAR-HSA-2318623 (Reactome)
HSPG2(22-4391)R-HSA-2396337 (Reactome)
HSPG2(22-4391)R-HSA-2396395 (Reactome)
HSPG2(22-4391)R-HSA-2426530 (Reactome)
HSPG2(22-4391)R-HSA-4084505 (Reactome)
HSPG2:DystroglycanArrowR-HSA-2396395 (Reactome)
HSPG2:FGF2(10-155),

Fibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB

homodimer
ArrowR-HSA-2396337 (Reactome)
HydroxylapatiteR-HSA-2424243 (Reactome)
IBSP:Collagen type I fibrilArrowR-HSA-4086204 (Reactome)
IBSPR-HSA-4086204 (Reactome)
Integrin alpha2beta1:Laminin-332ArrowR-HSA-349626 (Reactome)
Integrin

alpha3beta1,

alpha6beta4:Laminins-332, 511, 521, (211, 221)
ArrowR-HSA-216048 (Reactome)
Integrin

alpha3beta1,

alpha6beta4
R-HSA-216048 (Reactome)
Integrin

alpha5beta1:FN1

dimer
ArrowR-HSA-202723 (Reactome)
Integrin

alpha5beta1:FN1

dimer
R-HSA-2327746 (Reactome)
Integrin alpha5beta1:Fibronectin matrixArrowR-HSA-2327746 (Reactome)
Integrin

alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,

alphaVbeta1:Laminin-111
ArrowR-HSA-216051 (Reactome)
Integrin

alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,

alphaVbeta1
R-HSA-216051 (Reactome)
Integrin alpha6beta1:Laminin-211, 221, 332, 411, 512, 521ArrowR-HSA-3907292 (Reactome)
Integrin alpha7beta1:Laminin-211, 221, 411, 512, 521ArrowR-HSA-216058 (Reactome)
Integrin

alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,

alphaXbeta1
R-HSA-2681667 (Reactome)
Integrin alpha2beta1R-HSA-349626 (Reactome)
Integrin alpha5beta1R-HSA-202723 (Reactome)
Integrin alpha6beta1R-HSA-3907292 (Reactome)
Integrin alpha7beta1R-HSA-216058 (Reactome)
Integrin alphaVbeta1R-HSA-4086132 (Reactome)
Integrin alphaVbeta3R-HSA-4086200 (Reactome)
Integrins

alphaVbeta1, alphaVbeta3, alphaVbeta5,

alpha2bbeta3
R-HSA-2426471 (Reactome)
LRP4:MUSKR-HSA-2467633 (Reactome)
Laminin networkArrowR-HSA-2426676 (Reactome)
Laminin-111:Endostatin dimerArrowR-HSA-4084507 (Reactome)
Laminin-111R-HSA-216051 (Reactome)
Laminin-111R-HSA-2328145 (Reactome)
Laminin-111R-HSA-4084507 (Reactome)
Laminin-211, 221, 332, 411, 512, 521R-HSA-3907292 (Reactome)
Laminin-211, 221, 411, 512, 521R-HSA-216058 (Reactome)
Laminin-332R-HSA-349626 (Reactome)
Laminin-332R-HSA-3787997 (Reactome)
Laminins

with gamma-1,

gamma-3:Nidogens:Collagen type IV network
ArrowR-HSA-2426450 (Reactome)
Laminins

with gamma-1,

gamma-3:Nidogens:HSPG2
ArrowR-HSA-2426530 (Reactome)
Laminins with

alpha-1, -2 or

-5:HSPG2(22-4391)
ArrowR-HSA-4084505 (Reactome)
Laminins with alpha-1, -2 or -5R-HSA-4084505 (Reactome)
Laminins with

gamma-1, gamma-3:Nidogens

1,2
ArrowR-HSA-2327803 (Reactome)
Laminins with

gamma-1, gamma-3:Nidogens

1,2
R-HSA-2426450 (Reactome)
Laminins with

gamma-1, gamma-3:Nidogens

1,2
R-HSA-2426530 (Reactome)
Laminins with gamma-1, gamma-3R-HSA-2327803 (Reactome)
Laminins with gamma-1, gamma-3R-HSA-2426355 (Reactome)
Laminins with gamma-1R-HSA-2396124 (Reactome)
Laminins-332, 511, 521, (211, 221)R-HSA-216048 (Reactome)
Laminins:SulfatideArrowR-HSA-2396083 (Reactome)
LamininsR-HSA-2328129 (Reactome)
LamininsR-HSA-2396083 (Reactome)
LamininsR-HSA-2426676 (Reactome)
LecticansR-HSA-2424246 (Reactome)
Mn2+R-HSA-202723 (Reactome)
NCAM1, PTPRSR-HSA-2467659 (Reactome)
NRXN1R-HSA-2426263 (Reactome)
NTN4:Laminins with gamma-1, gamma-3ArrowR-HSA-2426355 (Reactome)
NTN4R-HSA-2426355 (Reactome)
Nidogens 1, 2R-HSA-2327803 (Reactome)
R-HSA-202723 (Reactome) Alpha5beta1 integrin was the first integrin shown to bind fibronectin (FN1). Unlike other FN1-binding integrins it is a specialist at this task. In solution FN1 occurs as a dimer. Binding to alpha5beta1 integrin stimulates FN1 self-association; blocking the RGD-cell binding domain of FN1 blocks fibril formation (Fogerty et al. 1990). FN1 binding is believed to induce integrin clustering, which promotes FN1-FN1 interactions. Integrin clustering is mediated by association between integrins and intracellular actin stress fibers (Calderwood et al. 2000). Binding of integrins to each of the monomers in the FN1 dimer pair is thought to trigger a conformational change in FN1 that exposes 'cryptic' FN1 binding sites that allow additional fibronectin dimers to bind without the requirement for pre-association with integrins (Singh et al. 2010). This non-covalent interaction may involve interactions with fibrillin (Ohashi & Erickson 2009). I1-5 functions as a unit that is the primary FN matrix assembly domain (Sottile et al. 1991) but other units are likely to be involved (Singh et al. 2010). Other integrins able to bind FN1 include alphaIIbBeta3, which is highly expressed on platelets where it predominantly binds fibrinogen leading to thrombus formation but also binds FN1 (Savage et al. 1996). Alpha4beta1 mediates cell-cell contacts and cell-matrix contacts through the ligands VCAM-1 and FN1, respectively (Humphries et al. 1995). Integrins alpha3beta1, alpha4beta7, alphaVbeta1, 3 (Johansson et al. 1997), 6 (Busk et al. 1992) and alpha8beta1 (Muller et al. 1995, Farias et al. 2005) are all able to bind FN1.

Tenacious binding of free fibronectin to cells leads to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. This process is enhanced in the presence of CEACAM molecules.
R-HSA-216048 (Reactome) The initial process of laminin (LM) deposition onto the cell surface depends upon interactions with the LG domain located at the alpha chain C-terminus. This domain contains binding sites for alpha-dystroglycan, sulfated glycolipids, heparan sulfate chains and integrins. The LM binding site for the major LM-binding integrins alpha6beta1, alpha6beta4, alpha3beta1 and alpha7beta1 (Belkin & Stepp 2000) is located in LG motifs 1-3 of LM alpha (LMA) chains (Hirosaki et al. 2000 - LMA3, unidentified integrin, Shang et al. 2001 - rat LMA3, human alpha3beta1, Smirnov et al. 2002 - LMA2 with mouse alpha6beta1, Talts et al. 2000 - mouse LMA4 with integrin alpha6beta1, Yu & Talts 2003 - mouse LMA5 with integrin alpha3beta1, Nishiuchi et al. 2006 - LMA1and LMA2 with alpha7beta1).

Recombinant integrins vary in their laminin specificities: integrins alpha3beta1 and alpha6beta4 have a clear specificity for LM-332 and -511/512, integrin alpha6beta1 has a broad specificity, binding all LM isoforms with a preference for LM-111, -332 and -511/521. Alpha7beta1 splice variants do not bind LM-332. Alpha7 isoform X1beta1 binds all LM except LM-332, with a preference for LM-211/221 and LM-511/521, while alpha7X2beta1 variant binds preferentially to LM-111 and LM-211/221. LM-511/521 has the highest affinity ligand for all LM-binding integrins except ofr alpha7 isoform X2beta1, while LM-411 has modest affinities for alpha6beta1 and alpha7 isoform X1beta1 (Nishiuchi et al. 2006 - all human reagents except mouse LM-111).

The N-terminal globular domains of LMA1 (Colognato-Pyke et al. 1995 - mouse LM, rat alpha1 and beta1 integrins) and alpha-2 chains (Colognato et al. 1997 - mouse LMA1, human LMA2, human integrins) can bind integrins alpha1beta1 and alpha2beta1. The N-terminal globular VI domains of LMA5 and LMA1 can bind integrin subunits alpha3, alpha2, alpha4, alpha6 (not LMA1) and beta1 (Nielsen & Yamada 2001 - using mouse LMA1 and LMA5 against human integrins). The IVa domain (L4a) domain of the LMA5 chain can bind integrin alphaVbeta3 (mouse LMA5, human integrin, Sasaki & Timpl 2001). The short arm of the LM gamma-2 chain has been reported to bind alpha2beta1 integrin (Decline & Rousselle 2001). The N-terminal globular domains of some alpha chains can also bind sulfatides, which may also link the LM molecules to the cell surface.

The relative importance of these interactions is unclear (Yurchenko & Patton 2009).

Integrins and dystroglycan indirectly connect the LM network to the actin cytoskeleton.
R-HSA-216051 (Reactome) The initial process of laminin (LM) deposition onto the cell surface depends upon interactions with the LG domain located at the alpha chain C-terminus. This domain contains binding sites for alpha-dystroglycan, sulfated glycolipids, heparan sulfate chains and integrins. The LM binding site for the major LM-binding integrins alpha6beta1, alpha6beta4, alpha3beta1 and alpha7beta1 (Belkin & Stepp 2000) is located in LG motifs 1–3 of LM alpha (LMA) chains (Hirosaki et al. 2000 - LMA3, unidentified integrin, Shang et al. 2001 - rat LMA3, human alpha3beta1, Smirnov et al. 2002 - LMA2 with mouse alpha6beta1, Talts et al. 2000 - mouse LMA4 with integrin alpha6beta1, Yu & Talts 2003 - mouse LMA5 with integrin alpha3beta1, Nishiuchi et al. 2006 - LMA1and LMA2 with alpha7beta1).

Recombinant integrins vary in their laminin specificities: alpha3beta1 and alpha6beta4 have a clear specificity for LM-332 and -511/512, integrin alpha6beta1 has a broad specificity, binding all LM isoforms with a preference for LM-111, -332 and -511/521. Alpha7beta1 variants do not bind LM-332. Alpha7 isoform X1beta1 binds all LM except LM-332, with a preference for LM-211/221 and LM-511/521, while alpha7 isoform X2beta1 binds preferentially to LM-111 and LM-211/221. LM-511/521 has the highest affinity for all LM-binding integrins except alpha7 isoform X2beta1, while LM-411 has low affinity only for alpha6beta1 and alpha7 isoform X1beta1 (Nishiuchi et al. 2006 - all human reagents except mouse LM-111).

The N-terminal globular domains of LMA1 (Colognato-Pyke et al. 1995 - mouse LM, rat alpha1 and beta1 integrins) and alpha-2 chains (Colognato et al. 1997 - mouse LMA1, human LMA2, human integrins) can bind integrins alpha1beta1 and alpha2beta1. The N-terminal globular VI domains of LMA5 and LMA1 can bind integrin subunits alpha3, alpha2, alpha4, alpha6 (not LMA1) and beta1 (Nielsen & Yamada 2001 - using mouse LMA1 and LMA5 against Cercopithecus aethiops integrins). The IVa domain (L4a) domain of the LMA5 chain can bind integrin alphaVbeta3 (mouse LMA5, human integrin, Sasaki & Timpl 2001). The LM gamma-2 chain has been reported to bind alpha2beta1 integrin (Decline & Rousselle 2001). The N-terminal globular domains of some alpha chains can also bind sulfatides, which may also link the LM molecules to the cell surface. The relative importance of these interactions is unclear (Yurchenko & Patton 2009). Integrins and dystroglycan indirectly connect the LM network to the actin cytoskeleton.

The alpha6beta1 integrin is one of the major platelet receptors for laminin-1 and plays an important role in supporting platelet adhesion under arterial rates of flow (Inoue et al. 2006).
R-HSA-216058 (Reactome) The initial process of laminin (LM) deposition onto the cell surface depends upon interactions with the LG domain located at the alpha chain C-terminus. This domain contains binding sites for alpha-dystroglycan, sulfated glycolipids, heparan sulfate chains and integrins. The LM binding site for the major LM-binding integrins alpha6beta1, alpha6beta4, alpha3beta1 and alpha7beta1 (Belkin & Stepp 2000) is located in LG motifs 1-3 of LM alpha (LMA) chains (Hirosaki et al. 2000 - LMA3, unidentified integrin, Shang et al. 2001 - rat LMA3, human alpha3beta1, Smirnov et al. 2002 - LMA2 with mouse alpha6beta1, Talts et al. 2000 - mouse LMA4 with integrin alpha6beta1, Yu & Talts 2003 - mouse LMA5 with integrin alpha3beta1, Nishiuchi et al. 2006 - LMA1and LMA2 with alpha7beta1).

Recombinant integrins vary in their laminin specificites: alpha3beta1 and alpha6beta4 have a clear specificity for LM-332 and -511/512, integrin alpha6beta1 has a broad specificity, binding all LM isoforms with a preference for LM-111, -332 and -511/521. Alpha7beta1 variants do not bind LM-332. Alpha7 isoform X1beta1 binds all LM except LM-332, with a preference for LM-211/221 and LM-511/521, while alpha7 isoform X2beta1 binds preferentially to LM-111 and LM-211/221. LM-511/521 has the highest affinity for all LM-binding integrins except alpha7 isoform X2beta1, while LM-411 has low affinity only for alpha6beta1 and alpha7 isoform X1beta1 (Nishiuchi et al. 2006 - all human reagents except mouse LM-111).

The N-terminal globular domains of LMA1 (Colognato-Pyke et al. 1995 - mouse LM, rat alpha1 and beta1 integrins) and alpha-2 chains (Colognato et al. 1997 - mouse LMA1, human LMA2, human integrins) can bind integrins alpha1beta1 and alpha2beta1. The N-terminal globular VI domains of LMA5 and LMA1 can bind integrin subunits alpha3, alpha2, alpha4, alpha6 (not LMA1) and beta1 (Nielsen & Yamada 2001 - using mouse LMA1 and LMA5 against Cercopithecus aethiops integrins). The IVa domain (L4a) domain of the LMA5 chain can bind integrin alphaVbeta3 (mouse LMA5, human integrin, Sasaki & Timpl 2001). The LM gamma-2 chain has been reported to bind alpha2beta1 integrin (Decline & Rousselle 2001). The N-terminal globular domains of some alpha chains can also bind sulfatides, which may also link the LM molecules to the cell surface.

The relative importance of these interactions is unclear (Yurchenko & Patton 2009).

Integrins and dystroglycan indirectly connect the LM network to the actin cytoskeleton.
R-HSA-2318623 (Reactome) In articular cartilage the major non-fibrous macromolecules are aggrecan, hyaluronan (HA) and hyaluronan and proteoglycan link protein 1 (HAPLN1). The high negative charge density of these molecules leads to the binding of large amounts of water (Bruckner 2006). HA is bound by large aggregating proteoglycans (the hyalectans). Aggrecan (ACAN) is predominantly expressed in cartilage, versican is widely distributed, while brevican and neurocan are largely restricted to nervous tissues. ACAN is ~90% carbohydrate. The core protein is highly glycosylated, mostly by the glycosaminoglycan (GAG) chains chondroitin sulphate (CS) and keratan sulphate (KS). Each ACAN molecule has ~100 CS chains of around 20 kDa and ~60 KS chains of 5-15 kDa. CS is attached to an extended domain between globular domains 2 and 3, while KS is widely distributed. The core protein also contains sites for the attachment of N-linked and O-linked oligosaccharides (Nilsson et al. 1982).

The G1 N-terminal domain of ACAN has a lectin-like binding site with high affinity for HA (Watanabe et al. 1997, Hardingham 2006). HA is a long unbranched, unsulphated GAG synthesized free from protein attachment by three HA synthases (Spicer & McDonald 1998). It has an average molecular weight of several million Da. HA content steadily rises in aging cartilage and can reach 10% of the total GAG. ACAN, HA and the small glycoprotein HAPLN1, known as Link protein, are found in huge multi-molecular aggregates comprised of numerous ACAN monomers non-covalently bound to HA, stabilized by HAPLN1 which forms a ternary complex with the G1 domain of ACAN and HA (Ratcliffe & Hardingham 1983, Grover & Roughley 1994, Kiani et al. 2002).
R-HSA-2327733 (Reactome) Fibronectin (FN1) binds many types of collagen, particularly when denatured (Ingham et al. 1985). A region of fibronectin known as the gelatin binding domain (GBD) is responsible for the interaction (Ingham et al. 1988); structures of this region bound to collagen alpha-1(I) are available (Erat et al. 2009, 2010). FN1 has been reported to bind isolated collagen alpha-1(I), alpha-2(I) and alpha-1(II) chains as well as several CNBr fragments (Ingham et al. 1988, 2002) indicating that there are multiple FN1 binding sites within each collagen chain (Dessau et al. 1978). FN1 conjugates can bind collagen types I through V (Bell & Engvall 1982), VII (Lapiere et al. 1994) and likely others. FN1 binds to aggregating collagen fibres, probably at the sites shown to bind denatured collagen, inhibiting the rate of collagen fibrillogenesis which may regulate the size of collagen fibres (Kleinman et al. 1981). Blocking the interaction of FN1 with collagen prevents collagen I fibril formation (McDonald et al. 1982). Newly assembled collagen fibrils colocalize with newly assembled FN1 fibrils (Li et al. 2003); FN1 fibril assembly and collagen fibril assembly may have common mechanistic elements (Kadler et al. 2008).
R-HSA-2327738 (Reactome) Discoidin domain receptors (DDRs) are a subfamily of receptor tyrosine kinases, the only members known to respond to an ECM component. DDR1 binds several of the major fibrillar collagens (types I, II, III, and V) and the non-fibrillar collagen IV (Shrivastava et al. 1997, Vogel et al. 1997, Hou et al. 2001). DDR proteins bind collagen as dimers (Leitinger 2003, 2011). DDR1 is mostly found in epithelial cells and leukocytes. It control developmental processes and regulates cell adhesion, migration, proliferation, and remodelling of the extracellular matrix by controlling the expression and activity of matrix metalloproteinases (Leitinger & Hohenester 2007).
R-HSA-2327746 (Reactome) The binding of integrins to each of the monomers in the FN1 dimer pair is thought to trigger a conformational change in FN1 that allows additional FN1 dimers to bind without pre-association with integrins (Singh et al. 2010). Domain I1-5 functions as the primary unit of FN1 matrix assembly (Sottile et al. 1991) but the process is not fully characterised and other FN1 units are likely to be involved (Singh et al. 2010). In this reaction an arbitrary 10 FN1 monomers are represented as being incorporated into the FN1 polymeric matrix.
R-HSA-2327803 (Reactome) Nidogen-1 and nidogen-2, also known as the entactins, are basement membrane glycoproteins with three globular domains (G1, G2, G3) separated by rod-like regions. They form stable complexes with laminins and collagen IV (Fox et al. 1991, Talts et al. 1999, Salmivirta et al. 2002), thereby acting as a major linking agent between these two networks in basement membrane ECM (Nischt et al. 2007). Interactions mediated by HSPG2 (perlecan) (Behrens et al. 2012) or HSPG2 and agrin (Hohenester & Yurchenko 2013) have been proposed as an alternative basis for the association of the laminin and collagen type IV networks in basement membrane. Nidogen-1 binds to the laminin-1 gamma subunit (Mayer et al. 1998). The gamma-2 chain of laminin-332 contains a homologous binding module. Nidogen-1 was reportedly unable to bind this laminin (Mayer et al. 1995), though an N-terminal fragment was able to bind (Sasaki et al. 2001). Laminin gamma-3 has been shown to bind to nidogen-1 and -2 with a lower affinity than that of gamma-1 (Gersdorff et al. 2005). The ab initio reconstruction of complexes between nidogen-1 and the laminin gamma-1 short arm confirms that this interaction is mediated solely by the C-terminal domains (Patel et al. 2013).
R-HSA-2327886 (Reactome) Small leucine rich repeat proteoglycans (SLRPs) are a family of extracellular glycoproteins that includes decorin (DCN), biglycan (BGN), fibromodulin, lumican and asporin (Hedbom & Heinegard 1993, Ezura et al. 2000, Schaefer & Iozzo 2008, Iozzo & Schaefer 2010). DCN inhibits cellular proliferation in a TGF-Beta-dependent manner in Chinese hamster ovary (CHO) cells (Yamaguchi et al. 1990), arterial smooth muscle cells (Fischer et al. 2001), human hepatic stellate cells (Shi et al. 2006) and fibroblasts (Zhang et al. 2007). DCN, BGN and fibromodulin can all bind to TGF-Beta (Hildebrand 1994). Binding is mediated by the leucine rich repeat suggesting that all members of the SLRP family have TGF-beta binding capability (Schönherr et al. 1998). DCN has independent binding sites for collagen and TGF-Beta (Schönherr et al. 1998, Cabello-Verrugio et al. 2012). DCN binding is thought to sequester TGF-Beta extracellularly, thereby diminishing its biological activity (Markmann et al. 2000). DCN treatment has beneficial effects in fibrotic disorders involving TGF-Beta overproduction (Border et al. 1992; Kolb et al. 2001, Baghy et al. 2012). BGN attenuates the proliferative actions of TGF-beta1 on fibroblasts (Kobayashi et al. 2003). DCN and BGN appear to mediate crosstalk between Toll-like receptors (TLRs), NOD-like receptors (NLRs) and transforming growth factor Beta (TGFBeta) receptors (reviewed in Moreth et al. 2012).
R-HSA-2327909 (Reactome) Decorin (DCN) belongs to the small leucine-rich repeat proteoglycan family (SLRPs) which also includes biglycan, fibromodulin (Hedlund et al. 1994 - binding to collagen II), lumican and asporin (Hedbom & Heinegard 1993, Ezura et al. 2000). Fibromodulin and lumican bind the same site while the binding site for decorin is distinct (Hedbom & Heinegard 1993). All appear to be involved in collagen fibril formation and matrix assembly (Ameye & Young 2002, Kalamajski & Oldberg 2010). DCN consists of a core protein of approximately 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), V (Whinna et al. 1993), VI (Bidanset et al. 1992) and XIV (Ehnis et al. 1997). It binds collagen I and II near the N-terminus, placing it at the 'd' band gap in the fibril structure (Kalamajski et al. 2007). The binding site for DCN on collagen XIV is in the NH2-terminal fibronectin type III repeat. In addition, an auxiliary binding site located COOH-terminally to this fibronectin type III repeat interacts with the glycosaminoglycan component of DCN. DCN binding regulates fibrillogenesis (Vogel et al. 1984, Orgel et al. 2006). One molecule of DCN interacts with four to six collagen molecules. The interaction is between collagen and the core protein, not the GAG chain, and is more likely to involve the monomeric, not dimeric form (Orgel et al. 2009). Fibronectin (Winnemoller et al. 1991) and thrombospondin-1 (Winnemoller et al. 1992) are also DCN interactors. DCN acts as a sink for all three isoforms of TGF-Beta, binding them when already bound to collagen (Markmann et al. 2000). Degradation of DCN by matrix metalloproteinases MMP-2, -3 or -7 results in 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-2328129 (Reactome) Dystroglycan (DG) is a cell-surface laminin receptor. In skeletal muscle it is a central component of the dystrophin-glycoprotein (DGC) complex (Ervasti & Campbell 1991). Mutations in components of the DGC render muscle fibres more susceptible to damage and lead to various types of muscle disorder such as Duchenne muscular dystrophy and limb-girdle muscular dystrophies (Straub & Campbell, 1997, Cohn & Campbell 2000). DG is present as non-covalently associated alpha and beta subunits following cleavage at Ser654. The extracellular alpha subunit binds to laminin-2 (merosin) in the muscle basement membrane while the membrane-associated beta subunit binds dystrophin, which associates with the actin cytoskeleton (Ervasti & Campbell 1993, Yamada et al. 1994, Talts et al. 1999). Alpha-DG also binds the carboxy-terminal G domains of laminin alpha-1 (Gee et al. 1993, Zhou et al. 2012) and alpha-5 (Yu & Talts 2003). G domains are relatively well conserved in all five alpha-laminin chains, so DG is likely to bind all laminin heterotrimers.
R-HSA-2328145 (Reactome) Type IV collagen (Yurchenco & Furthmayr 1984) and laminin (Yurchenco et al. 1985,1992, Cheng et al. 1997) can self-assemble in vitro, forming lattice-like polymeric networks which resemble laminin-collagen matrices observed in vivo (Timpl & Brown 1996). Purified laminins are the only basement membrane component able to assemble on cell surfaces in the absence of other components (McKee et al. 2007). Laminin knockouts prevent basement membrane assembly, arresting development at a much earlier stage than knockouts of other ECM components such as collagen IV, nidogens (entactin), perlecan or agrin (Yurchenko et al. 2004). This suggests a regulatory function for the laminin network. Laminin molecules bind to each other in a three-way interaction involving the LN domains located at the end of the three short arms. Each interaction involves one each of alpha, beta and gamma laminin subunits (Yurchenko & Cheng 1993, McKee et al. 2007) forming a polygonal structure (Yurchenko et al. 1992).

In the basement membrane collagen type IV and laminin are found in an approximately 1:1 molar ratio (Kleinman et al. 1986). Binding between laminin and collagen type IV is primarily facilitated by nidogen (Aumailley et al. 1989, Fox et al. 1991), but direct binding has been observed (Charonis et al. 1985, Rao et al. 1985). Laminin-111 (laminin-1) binds to type IV collagen through its short arms (Laurie et al. 1986).
R-HSA-2396079 (Reactome) The somatomedin B domain of vitronectin (VTN) binds to and stabilizes plasminogen activator inhibitor-1 (PAI1) (Declerck et al. 1988). PAI1 is the principal physiological inhibitor of both tissue (tPA) and urokinase (uPA) plasminogen activators and a key regulator of the fibrinolytic system; the stabilization of PAI1 by VTN thereby regulates proteolysis of fibrin (Zhou et al. 2003). Elevated PAI1 activity is associated with coronary thrombosis (Hamsten et al. 1987) and poor prognosis in many cancers.
R-HSA-2396083 (Reactome) Sulfated glycolipids (SGs) such as the sulfatides bind strongly to the LG domains of laminin (Roberts et al. 1985, 1986, Ishizuka 1997). The most common SG, HSO3-3galactosylBeta-1ceramide (galactosyl-3-sulfate ceramide or sulfatide) is highly expressed in developing and adult peripheral nerves (Mirsky et al. 1990), Schwann cells, kidney and other tissues. SGs are thought to mediate or enhance the cell surface anchorage of laminins, possibly by allowing the short arms to bind the cell surface in addition to the LG domains (Li et al. 2005, Yurchenko & Patton 2009).
R-HSA-2396113 (Reactome) Alpha-dystroglycan (DG) binds G domain-like sequences in other extracellular matrix molecules such as AGRN (agrin) (Gee et al. 1994, Campanelli et al. 1994, Sugiyama et al. 1994, Yamada et al. 1996, Gesemann et al. 1996) and HSPG2 (perlecan) (Peng et al. 1998, Talts et al. 1999). DG knockout mice exhibit severe disruption of basement membranes and embryonic stem cells fail to deposit laminin, suggesting a role for DG in laminin matrix formation (Henry & Campbell 1998). Conditional ablation of DG expression in cultured mammary epithelial cells disrupted laminin-111-induced polarity and beta-casein production, and abolished laminin binding and assembly on the cell surface. Dystroglycan re-expression restored these deficiencies (Weir et al. 2006).
R-HSA-2396124 (Reactome) Agrin (AGRN) is a large (>400 kDa) multi-domain heparan sulfate proteoglycan found in basement membranes. It is a critical organizer of postsynaptic differentiation at the skeletal neuromuscular junction; synaptogenesis is profoundly disrupted in its absence (Gautam et al. 1996). Two alternate N-termini exist with differential expression, tissue localization and function. The predominant longer LN form (Burgess et al. 2000) starts with a secretion signal sequence and a laminin-binding domain (Denzer et al. 1995, Kammerer et al. 1999); the shorter SN form associates with the plasma membrane (Burgess et al. 2000, Neumann et al. 2001). Following the SN or LN regions are 8 follistatin repeats, known to bind growth factors and inhibit proteases in other proteins. The central region has two repeats homologous to domain III of laminin. The C-terminal portion, which is responsible for the molecule's known signalling functions, contains four EGF repeats and three LG (G) domains homologous to those found in laminin alpha chains, neurexins and slits (Timpl et al. 2000).

The N-terminus of the LN form of AGRN binds to the laminin gamma1 subunit (Denzer et al. 1997, Kammerer et al. 1999, Mascarenhas et al. 2003). This may indirectly bind AGRN to integrins on the cell surface (Bezakova & Ruegg 2003).
R-HSA-2396337 (Reactome) Perlecan (HSPG2) is a modular proteoglycan primarily located in the basement membranes of vascular tissues. It is involved in several developmental processes, both during embryogenesis and in human diseases such as cancer and diabetes (Iozzo et al. 1994). HSPG2 can self-aggregate into dimeric or multimeric forms (Yurchenco et al. 1987) and is involved in heterotypic interactions with numerous extracellular macromolecules (Whitelock et al. 2008, Perlecan entry in MatrixDB). HSPG2's GAG chains mediate interactions with fibroblast growth factor-2 (Vigny et al. 1988, Knox et al. 2002), and nidogens (Entactins, represented elsewhere). The core protein binds fibronectin (Isemura et al. 1987, Heremans et al. 1990, Vlodavsky et al. 1991), transthyretin (Smeland et al. 1997) and platelet-derived growth factor A and B homodimers (Göhring et al. 1998).
R-HSA-2396370 (Reactome) Vitronectin (VTN) is a major plasma glycoprotein of 75 kDa, circulating at approximately 0.2 mg/ml in humans. It interacts with collagen types I, II, III, IV, V, and VI (Gebb et al. 1986). Deglycosylation enhances VTN binding to collagen and is associated with VTN multimerization (Uchibori-Iwaki et al. 2000, Sano et al. 2007).
R-HSA-2396395 (Reactome) HSPG2 (perlecan) is a modular proteoglycan primarily located in the basement membranes of vascularized tissues. It is involved in several developmental processes, both during embryogenesis and in human disease such as cancer and diabetes (Iozzo et al. 1994). Domain V of the core protein binds alpha-dystroglycan (Talts et al. 1999), which in vivo forms a membrane-associated heterodimer with beta-dystroglycan (Peng et al. 1998).
R-HSA-2424243 (Reactome) Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40, binds Collagen type I, hydroxyapatite and Ca2+, suggesting a role in the mineralization of bone and cartilage (Termine et al. 1981). It is expressed by osteoblasts, odontoblasts, and many other cell types (Romanowski et al. 1990, Mundlos et al. 1992, Papagerakis et al. 2002). SPARC expression has been used to follow the progression of osteoblast cytodifferentiation.
R-HSA-2424246 (Reactome) Tenascins are a family of 4 oligomeric extracellular glycoproteins, tenascin (TN) C, R, X, and N (also called W). In rotary shadowing images TNC is seen as a symmetrical structure called a hexabrachion (Erickson & Iglesias 1984). This hexamer is formed from initial trimers (Kammerer et al. 1988). All members of the family are believed able to form trimers but only C, R and W have the extra cysteine required for form hexamers. All have amino-terminal heptad repeats, epidermal growth factor (EGF)-like repeats, fibronectin type III domain repeats, and a carboxyl-terminal fibrinogen-like globular domain (Hsia & Schwartzbauer 2005). TNC was the first family member to be discovered and is the best characterised. Its subunits vary greatly in size (between 190 and 330 kDa of the tenascin-C monomer) due to glycosylation and splicing isoforms (Joester & Faissner 1999). During embryonic development TNC is expressed in neural, skeletal, and vascular tissues. In adults it is detectable only in tendon and tissues undergoing remodeling processes such as wound repair and neovascularization, or in pathological processes such as inflammation and tumorigenesis (Midwood & Orend 2009). TNR forms dimers and trimers (Norenberg et al. 1992) and is expressed only in the developing and adult central nervous system. TNC and TNR-null mice (single and double knock-outs) have surprisingly normal gross phenotypes, but exhibit behavioural and wound healing abnormalities (Mackie & Tucker 1999, Montag-Sallaz & Montag 2003). TNX is the largest member of the family and is widely expressed during development, but in adults is limited to musculoskeletal, cardiac, and dermal tissue. It can form trimers, though it lacks the amino-terminal cysteine residues involved in hexamer formation. It is clearly associated with a variant of a heritable connective tissue disorder known as Ehler-Danlos Syndrome, which is associated with fibrillar collagen defects (Burch et al. 1997, Mao et al. 2002). TNY is thought to be an avian orthologue of TNX (Chiquet-Ehrismann 2004). TNN, first identified in zebrafish (Weber et al. 1998), is the least well characterized member of the tenascin family. It forms hexamers (Degen et al. 2007) and is expressed in developing skeletal tissue and neural crest cells, a pattern that partially overlaps with TNC.

TNC and TNR bind to members of the lectican family, a class of extracellular chondroitin sulfate proteoglycans consisting of aggrecan, versican, brevican and neurocan. TNC binds aggrecan (Lundell et al. 2004), versican (Tsujii et al. 2006) and neurocan (Milev et al. 1994, Grumet et al. 1994, Rauch et al. 1997). TNR binds aggrecan (Aspberg et al. 1997, Lundell et al. 2004), versican (Aspberg et al. 1995, 1997), brevican Aspberg et al. 1997, Hagihara et al. 1999) and neurocan (Aspberg et al. 1997).
R-HSA-2424252 (Reactome) Cartilage oligomeric matrix protein (COMP, thrombospondin-5) is a 524-kDa pentameric glycoprotein expressed primarily in cartilage, tendon, ligament and synovium. In adult cartilage, COMP is located primarily in the inter-territorial matrix between chondrocytes (Murphy et al. 1999). The mature protein is pentameric with each monomer linked to its neighbour by a disulphide bond, located at the amino terminus of the protein (Hedbom et al. 1992, Morgelin et al. 1992). COMP binds directly to collagen types I, II and IX (Rosenberg et al. 1998, Thur et al. 2001) at the fibril periphery. In addition it binds fibronectin (FN1) (Di Cesare et al. 2002), matrilins 1, 3 and 4 (Mann et al. 2004), and through the glycosaminoglycans heparan sulphate and chondroitin sulphate to aggrecan (Hauser et al. 1996, Chen et al. 2007).
Mutations in COMP lead to pseudoachondroplasia and multiple epiphyseal dysplasia (Jackson et al. 2012). COMP binding to FN1 and probably to other partners requires the presence of the divalent cations Ca2+, Mg2+ or Mn2+. Each COMP subunit binds approximately 10 calcium ions (Chen et al. 2000).
R-HSA-2426263 (Reactome) Dystroglycan binds specifically to a subset of neurexin LNS domains in a tight interaction that requires the glycosylation of dystroglycan and is regulated by neurexin alternative splicing. Alpha-dystroglycan binds G domain-like sequences in neurexin-1-alpha (NRXN1) (Sugita et al. 2001).
R-HSA-2426355 (Reactome) Netrins are a family of extracellular proteins that include axonal guidance factors. They have N-terminal domains that are homologous to the LN domains of laminins. Netrin-4 (NTN4), but not other forms of netrin, bind laminin gamma-1 and gamma-3 short arms in the basement membrane, suggesting a role in regulating basement membrane formation (Schneiders et al. 2007). NTN4 has been found associated in a functional complex with laminin gamma-1 chain and integrin alpha6beta1, suggesting a role in regulation of neurogenesis in the olfactory system (Staquicini et al. 2009).
R-HSA-2426450 (Reactome) Laminin-bound nidogens can bind to type IV collagen (Aumailey et al. 1989, 1993, Fox et al. 1991, Reinhardt et al. 1993, Ries et al. 2001, Bechtel et al. 2012).

Basement membrane formation involves self-assembly of laminin and of collagen IV into two independent networks (Yurchenco & Schittny 1990, Timpl & Brown 1996) that are connected by nidogen (Fox et al. 1991, Aumailley & Smyth 1998, Aumailey et al. 2000) and the heparan sulfate chains of both perlecan and agrin (Hohenester & Yurchenko 2013).
R-HSA-2426471 (Reactome) Integrin alphaVbeta3 is sometimes referred to as the 'vitronectin receptor'. Vitronectin interacts with integrins alphaVbeta1 (Marshall et al. 1995), alphaVbeta3 (Pytela et al. 1985, Boettiger et al. 2001), alphaVbeta5 (Panetti & McKeown-Longo 1993) and alpha2b beta3 (Pytela et al. 1986) through Arg-Gly-Asp (RGD) cell binding sequences.

Endothelial cells lining the microvascular wall form a semi-permeable barrier to the movement of blood components. The attachment of endothelial cells to the extracellular matrix (ECM) is largely mediated by transmembrane integrins which recognize short sequence motifs such as Arg-Gly-Asp (RGD) in many ECM proteins.

Integrin alpha5beta1 and alphaVbeta3 bind to the ECM proteins fibronectin and vitronectin respectively. Both are critical for the establishment and stabilization of endothelial monolayers (Cheng & Kramer 1989). Synthetic peptides that compete with ECM proteins for the integrins or antibodies directed against alpha5beta1 and alphaVbeta3 cause endothelial cell detachment (Hayman et al. 1985, Pierschbacher & Ruoslahti 1987).
R-HSA-2426530 (Reactome) The IG3 repeat in domain IV of perlecan is the principal site of interaction with nidogens, binding to the G2 domain (Mayer et al. 1998, Hopf et al. 2001). Domain V of perlecan also binds to nidogen (Brown et al. 1997). Nidogen-1 in turn binds to the laminin gamma1-subunit (Mayer et al. 1998), providing a bridge between the two proteins (Hopf et al. 1999, 2001, Kvansakul et al. 2001).
R-HSA-2426676 (Reactome) The principal structural elements of basement membrane are laminin (LM) and collagen IV. These form distinct networks that become noncovalently interconnected by nidogen and perlecan, both of which are able to form irregular polymers (Breitkreutz et al. 2013).

LM polymeric networks can self-assemble even in the absence of other basement membrane components (Yurchenco et al. 1992) suggesting a key developmental role. Polymerization in vivo occurs at the cell surface, to which LMs are anchored through direct or indirect interactions with cellular receptors, dystroglycan or integrins, and possibly other receptors (Hohenester & Yurchenco 2013).

Receptor-engaged LM exceeds the critical concentration for self-assembly (Colognato & Yurchenco 2000).

The three short arms of the cross-shaped LM molecule form the nodes in the polymeric network, with a strict requirement for one each of alpha, beta and gamma arms (Hohenester & Yurchenco 2013). A surface loop, strictly conserved in the LN domains of all alpha chains, is required for stable ternary association with the beta and gamma short arms (Hussain et al. 2011).
R-HSA-2465883 (Reactome) Vitronectin (VTN) is a major plasma glycoprotein of 75 kDa, circulating at approximately 0.2 mg/ml in humans. It interacts with collagen types I, II, III, IV, V, and VI (Gebb et al. 1986). Deglycosylation enhances VTN binding to collagen and is associated with VTN multimerization (Uchibori-Iwaki et al. 2000, Sano et al. 2007).
R-HSA-2465890 (Reactome) Discoidin domain receptors (DDRs) are a subfamily of receptor tyrosine kinases, the only members known to respond to an ECM component. DDR2 binds the major fibrillar collagens types I, II, III, and V) and the non-fibrillar collagen X (Shrivastava et al. 1997, Vogel et al. 1997, Leitinger & Kwan 2006). DDR proteins bind collagen as dimers (Leitinger 2003, 2011). DDR2 is confined to mesenchymal cells where it controls developmental processes and regulates cell adhesion, migration, proliferation, and remodelling of the extracellular matrix by controlling the expression and activity of matrix metalloproteinases (Leitinger & Hohenester 2007).
R-HSA-2466106 (Reactome) Biglycan is a member of the small leucine-rich repeat proteoglycan family (SLRPs) which also includes decorin, fibromodulin (Hedlund et al. 1994 - binding to collagen II), lumican and asporin (Hedbom & Heinegard 1993, Ezura et al. 2000). All appear to be involved in collagen fibril formation and matrix assembly (Ameye & Young 2002).

Biglycan binds collagen types I (Schönherr et al. 1995), II (Bovine, using pig byglycan - Vynios et al. 2001, Bovine, using bovine biglycan - Douglas et al. 2008), III (Bovine, using bovine biglycan - Douglas et al. 2008), VI (Wiberg et al. 2001, 2002, human) and IX (Chen et al. 2006 - species source of collagen/biglycan unknown).
R-HSA-2466238 (Reactome) Biglycan (BGN) is a member of the small leucine-rich repeat proteoglycan family (SLRPs) which also includes decorin, fibromodulin (Hedlund et al. 1994 - binding to collagen II), lumican and asporin (Hedbom & Heinegard 1993, Ezura et al. 2000). All appear to be involved in collagen fibril formation and matrix assembly (Ameye & Young 2002).

BGN-deficient mice exhibit larger and irregular fibrils leading to thin dermis and reduced bone mass (Corsi et al. 2002, Xu et al. 1998). BGN binds collagen types I (Schönherr et al. 1995), II (Bovine, using pig BGN - Vynios et al. 2001, Bovine, using bovine BGN - Douglas et al. 2008), III (Bovine, using bovine BGN - Douglas et al. 2008), VI (Wiberg et al. 2001) and IX (Chen et al. 2006 - species source of collagen/BGN unknown).
R-HSA-2467633 (Reactome) Agrin (AGRN) is a large multidomain heparan sulfate proteoglycan found in basement membranes, named for its ability to promote aggregation of AChR clusters on the muscle surface directly beneath the nerve terminal (Nitkin et al. 1987). It is a critical organizer of postsynaptic differentiation at the skeletal neuromuscular junction; synaptogenesis is profoundly disrupted in its absence (Gautam et al. 1996). Two alternate N termini exist with differential expression, tissue localization and function. The predominant longer LN form (Burgess et al. 2000) starts with a secretion signal sequence and a laminin-binding domain (Denzer et al. 1995, Kammerer et al. 1999); the shorter SN form associates with the plasma membrane (Burgess et al. 2000, Neumann et al. 2001). Following the SN or LN regions are 8 follistatin repeats, known to bind growth factors and inhibit proteases in other proteins. The central region has two repeats homologous to domain III of laminin. The C-terminal portion, which is responsible for the molecule's known signaling functions, contains four EGF repeats and three LG (G) domains homologous to those found in laminin alpha chains, neurexins and slits (Timpl et al. 2000).


AGRN binds a complex of the tyrosine kinase receptor MuSK, which is responsible for mediating agrin's ability to cluster AChR (Glass et al. 1996, Sanes & Lichtman 2001, Burden et al. 2003) and the coreceptor LRP4 (Kim et al. 2008, Zhang et al. 2008, Zong et al. 2012).
R-HSA-2467659 (Reactome) Several agrin (AGRN) ligands require the presence of heparan-sulfate sidechains and are probably mediated by them. Membrane-associated AGRN ligands include the neural cell adhesion molecule NCAM1 (Burg et al. 1995, Tsen et al. 1995, Cole & Halfter 1996 - represented in REACT_19071) and receptor protein tyrosine phosphatase sigma (PTPRS) (Aricescu et al. 2002).
R-HSA-2467665 (Reactome) Several agrin (AGRN) ligands require the presence of heparan-sulfate GAG sidechains and probably represent interactions with them. Extracellular ligands include Beta-amyloid (Donahue et al. 1999, Cotman et al. 2000). Other ligands (unconfirmed in humans) include alpha-synuclein fibrils (chicken - Liu et al. 2005), HB-GAM/pleiotropin (Dagget et al. 1996), thrombospondin and FGF2 (Cotman et al. 1999).
R-HSA-2467716 (Reactome) Agrin (AGRN) is a multidomain heparan sulfate proteoglycan found in basement membranes, named for its ability to promote aggregation of AChR clusters on the muscle surface directly beneath the nerve terminal (Nitkin et al. 1987). It is a critical organizer of postsynaptic differentiation at the skeletal neuromuscular junction; synaptogenesis is profoundly disrupted in its absence (Gautam et al. 1996, Daniels 2012). Two alternate N-termini exist with differential expression, tissue localization and function. The secreted and predominant longer LN form (Burgess et al. 2000) starts with a secretion signal sequence and a laminin-binding domain (Denzer et al. 1995, Kammerer et al. 1999); the shorter SN form associates with the plasma membrane (Burgess et al. 2000, Neumann et al. 2001). Following the SN or LN regions are 8 follistatin repeats, known to bind growth factors and inhibit proteases in other proteins. The central region has two repeats homologous to domain III of laminin. The C-terminal portion, which is responsible for the molecule's known signaling functions, contains four EGF repeats and three LG (G) domains homologous to those found in laminin alpha chains, neurexins and slits (Timpl et al. 2000).

The LG domains of AGRN bind alpha-dystroglycan (Yamada et al. 1996, Gee et al. 1994, Bowen et al. 1996, Campanelli et al. 1996, Gesemann et al. 1996, Hopf & Hoch 1996).
R-HSA-2545196 (Reactome) Prior to matrix formation, fibronectin (FN1) exists as a protein dimer. Often the two peptide chains are differentially-spliced variants. The chains are linked by a pair of C-terminal disulfide bonds which are essential for subsequent multimerization (Schwarzbaur 1991). FN1 monomers have a molecular weight of 230-270 kDa depending on the alternative splicing and contain three types of repeating domains, type I, II, and III. Type I and II domains are stabilized by intra-chain disulfide bonds. FN1 dimer binding to alpha5beta1 integrin stimulates self-association.
R-HSA-2681667 (Reactome) Tenascins are a family of 4 oligomeric extracellular glycoproteins, tenascin (TN) C, R, X, and W. In rotary shadowing images TNC is seen as a symmetrical structure called a hexabrachion (Erickson & Iglesias 1984). This hexamer is formed from initial trimers (Kammerer et al. 1988). All members of the family are believed able to form trimers but only C, R and W have the extra cysteine required for form hexamers. All have amino-terminal heptad repeats, epidermal growth factor (EGF)-like repeats, fibronectin type III domain repeats, and a carboxyl-terminal fibrinogen-like globular domain (Hsia & Schwartzbauer 2005). TNC was the first family member to be discovered and is the best characterised (Midwood et al. 2011). Its subunits vary greatly in size (between 190 and 330 kDa of the tenascin-C monomer) due to glycosylation and splicing isoforms (Joester & Faissner 1999). During embryonic development TNC is expressed in neural, skeletal, and vascular tissues. In adults it is detectable only in tendon and tissues undergoing remodeling processes such as wound repair and neovascularization, or in pathological processes such as inflammation and tumorigenesis (Midwood & Orend, 2009).

TNC binds several integrins including alpha2beta1 (Sriramararo et al. 1993), alphaVbeta6 (Yokosaki et al. 1996), alphaVbeta3 (Sriramararo et al. 1993, Yokosaki et al. 1996), alpha9beta1 (Yokosaki et al. 1996), alphaXbeta1 (Probstmeier & Peshva 1999), alpha8beta1 (Schnapp 1995) and alpha7beta1 (Mercado et al. 2004).
R-HSA-2681681 (Reactome) Tenascins are a family of 4 oligomeric extracellular glycoproteins, tenascin (TN) C, R, X, and N (also called W). In rotary shadowing images TNC is seen as a symmetrical structure called a hexabrachion (Erickson & Iglesias 1984). This hexamer is formed from initial trimers (Kammerer et al. 1988). All members of the family are believed able to form trimers but only C, R and N have the extra cysteine required for form hexamers. All have amino-terminal heptad repeats, epidermal growth factor (EGF)-like repeats, fibronectin type III domain repeats, and a carboxyl-terminal fibrinogen-like globular domain (Hsia & Schwartzbauer 2005). TNC was the first to be discovered and is the best characterised. Its subunits vary greatly in size due to glycosylation and splicing isoforms (Joester & Faissner 1999). During embryonic development TNC is expressed in neural, skeletal, and vascular tissues. In adults it is detectable only in tendon and tissues undergoing remodeling processes such as wound repair and neovascularization, or in pathological processes such as inflammation and tumorigenesis. TNR forms dimers and trimers (Norenberg et al. 1992) and is expressed only in the central nervous system. TNC and TNR-null mice (single and double knock-outs) have surprisingly normal gross phenotypes, but exhibit behavioural and wound healing abnormalities (Mackie & Tucker 1999, Montag-Sallaz & Montag 2003). TNX is the largest member of the family and is widely expressed during development, but in adults is limited to musculoskeletal, cardiac, and dermal tissue. It can form trimers, though it lacks the amino-terminal cysteine residues involved in hexamer formation. It is clearly associated with a variant of a heritable connective tissue disorder known as Ehler-Danlos Syndrome, which is associated with fibrillar collagen defects (Burch et al. 1997, Mao et al. 2002). TNY is thought to be an avian orthologue of TNX (Chiquet-Ehrismann 2004). TNN, first identified in zebrafish (Weber et al. 1998), is the least well characterized member of the tenascin family. It forms hexamers (Degen et al. 2007) and is expressed in developing skeletal tissue and neural crest cells, a pattern that partially overlaps with TNC.

TNC and TNR bind with high affinity to fibronectin (FN) (Chiquet-Ehrismann et al. 1991, Chung et al. 1995, Chung & Erickson 1997, Hauzenberger et al. 1999, Ingham et al. 2004, To & Midwood 2011, Pesheva et al. 1994), modulating the cell adhesion function of FN either by binding or restricting access of FN to integrin binding sites (Lightner & Erickson 1990) or by binding to cell receptors and altering their responsiveness to FN (Prieto et al. 1992, Fischer et al. 1997). The interaction of Tenascin and FN impacts tissue structure by controlling the assembly, maintenance, and turnover of the ECM at the cell surface (To & Midwood 2010).
R-HSA-349626 (Reactome) Colonic epithelial cells use integrin alpha2beta1 to adhere to Laminin-5.
R-HSA-3787997 (Reactome) Laminin-332 (laminin-5) consists of laminin alpha-3, beta-3 and gamma-2 chains. It is epithelial-basement membrane specific. It directly interacts with the NC1 domain of Collagen type VII through the N-terminus of the beta-3 laminin subunit and, to a lesser extent, the gamma-2 laminin subunit (Rousselle et al. 1997, Chen et al. 1999, Brittingham et al. 2006).
R-HSA-3907292 (Reactome) The initial process of laminin (LM) deposition onto the cell surface depends upon interactions with the LG domain located at the alpha chain C-terminus. This domain contains binding sites for alpha-dystroglycan, sulfated glycolipids, heparan sulfate chains and integrins. The LM binding site for the major LM-binding integrins alpha6beta1, alpha6beta4, alpha3beta1 and alpha7beta1 (Belkin & Stepp 2000) is located in LG motifs 1-3 of LM alpha (LMA) chains (Hirosaki et al. 2000 - LMA3, unidentified integrin, Shang et al. 2001 - rat LMA3, human alpha3beta1, Smirnov et al. 2002 - LMA2 with mouse alpha6beta1, Talts et al. 2000 - mouse LMA4 with integrin alpha6beta1, Yu & Talts 2003 - mouse LMA5 with integrin alpha3beta1, Nishiuchi et al. 2006 - LMA1and LMA2 with alpha7beta1).

Recombinant integrins vary in their laminin specificities: alpha3beta1 and alpha6beta4 have a clear specificity for LM-332 and -511/512, integrin alpha6beta1 has a broad specificity, binding all LM isoforms with a preference for LM-111, -332 and -511/521. Alpha7beta1 variants do not bind LM-332. Alpha7 isoform X1beta1 binds all LM except LM-332, with a preference for LM-211/221 and LM-511/521, while alpha7 isoform X2beta1 binds preferentially to LM-111 and LM-211/221. LM-511/521 has the highest affinity for all LM-binding integrins except alpha7 isoform X2beta1, while LM-411 has low affinity only for alpha6beta1 and alpha7 isoform X1beta1 (Nishiuchi et al. 2006 - all human reagents except mouse LM-111).

The N-terminal globular domains of LMA1 (Colognato-Pyke et al. 1995 - mouse LM, rat alpha1 and beta1 integrins) and alpha-2 chains (Colognato et al. 1997 - mouse LMA1, human LMA2, human integrins) can bind integrins alpha1beta1 and alpha2beta1. The N-terminal globular VI domains of LMA5 and LMA1 can bind integrin subunits alpha3, alpha2, alpha4, alpha6 (not LMA1) and beta1 (Nielsen & Yamada 2001 - using mouse LMA1 and LMA5 against Cercopithecus aethiops integrins). The IVa domain (L4a) domain of the LMA5 chain can bind integrin alphaVbeta3 (mouse LMA5, human integrin, Sasaki & Timpl 2001). The LM gamma-2 chain has been reported to bind alpha2beta1 integrin (Decline & Rousselle 2001). The N-terminal globular domains of some alpha chains can also bind sulfatides, which may also link the LM molecules to the cell surface.
The relative importance of these interactions is unclear (Yurchenko & Patton 2009).

Integrins and dystroglycan indirectly connect the LM network to the actin cytoskeleton.
R-HSA-4084501 (Reactome) The NC1 domain of collagen VII is able to bind collagen type IV and laminin-322 (laminin-5) (Brittingham et al. 2006). This facilitates stabilization of the basement membrane structure.
R-HSA-4084505 (Reactome) Laminins bind to HSPG2 (perlecan) through interactions with its heparan sulfate sidechains (Battaglia et al. 1992, Behrens et al. 2012). The E3 fragment of laminin (containing the C-terminal LG4-LG5 domain pair) harbours binding sites for heparin, sulfatides and the cell surface receptor dystroglycan (Andac et al. 1999, Tisi et al. 2000) This interaction, rather than nidogen-mediated association, has been proposed to be the structural basis for association of the laminin and collagen type IV networks in basement membrane (Behrens et al. 2012). Alternatively the heparan sulfate chains of both perlecan and agrin might extend from a nidogen-containing laminin network to bind type IV collagen (Hohenester & Yurchenko 2013).
R-HSA-4084507 (Reactome) Endostatin is an anti-angiogenic and motility-inducing factor produced by proteolytic cleavage within the NC1 domain of collagen type XVIII. It is bound by all three short arms of laminin-111 (Javaherian et al. 2002). Laminin-111 complexes strongly with the NC1 trimeric domain or endostatin dimer, but only weakly with endostatin monomer.
R-HSA-4086132 (Reactome) DPP (also called “phosphophoryn�) is a highly acidic protein and is the major noncollagenous matrix component of dentin (13,–,15). The molecule is so-called because it is considered to be a “phosphate carrier� (16). DPP is exceedingly rich in aspartic acid and serine residues ((DSS)n), and about 90% of the serine residues are phosphorylated (17, 18). This enables DPP to have a strong affinity for calcium ion, and thus it significantly promotes the growth of hydroxyapatite crystals when bound to collagen fibrils in vitro.
R-HSA-4086200 (Reactome) Dentin matrix phosphoprotein 1 (DMP1) is a non-collagenous, acidic extracellular matrix protein expressed chiefly in bone and dentin. DMP1 acts via interaction with alphaVbeta3 integrin (Wu et al. 2011).
R-HSA-4086204 (Reactome) Bone sialoprotein 2 (IBSP) is an anionic phosphorylated glycoprotein expressed almost exclusively in mineralized tissues. It is a potent nucleator of hydroxyapatite formation. The binding of IBSP to collagen is thought to be important for the initiation of bone mineralization and in the adhesion of bone cells to the mineralized matrix (Fujisawa et al. 1995, Tye et al. 2005).
R-HSA-8941234 (Reactome) SH3PXD2A (TKS5, FISH) was discovered as an adaptor protein and Src substrate (Lock et al. 1998). It is essential for invadopodia and podosome formation in many different cell types. It is not required for precursor initiation but is needed for precursor stabilization (Sharma et al. 2013). It contains a phox homology (PX) domain that binds the membrane phosphoinositides PI3P and PI(3,4)P2 (Abram et al. 2003) In Src-transformed NIH 3T3 cells, TKS5 and PI(3,4)P2 localize to podosomes via a GRB2-dependent mechanism (Oikawa et al. 2008).

TKS5 directly binds to the ADAM family proteases 12, 15, and 19 (Abram et al. 2003), N-WASP, dynamin-2, and Grb2 (Oikawa et al. 2008) and NCK1 and 2 (Styli et al. 2009). In vivo, decreased Tks5 expression correlates with reductions in tumor growth, metastasis, and angiogenesis (Blouw et al. 2008).


SERPINE1R-HSA-2396079 (Reactome)
SH3PXD2A:PI(3,4)P2:ADAM12,ADAM15,ADAM19ArrowR-HSA-8941234 (Reactome)
SH3PXD2A:PI(3,4)P2R-HSA-8941234 (Reactome)
SLRPs:TGF betaArrowR-HSA-2327886 (Reactome)
SLRPsR-HSA-2327886 (Reactome)
SPARCR-HSA-2424243 (Reactome)
SulfatideR-HSA-2396083 (Reactome)
TGF betaR-HSA-2327886 (Reactome)
TNC:Integrin

alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,

alphaXbeta1
ArrowR-HSA-2681667 (Reactome)
Tenascin-C hexamerR-HSA-2681667 (Reactome)
Tenascins C, R, (X,

N):Fibronectin

matrix
ArrowR-HSA-2681681 (Reactome)
Tenascins C, R, (X, N):LecticansArrowR-HSA-2424246 (Reactome)
Tenascins C, R, (X, N)R-HSA-2424246 (Reactome)
Tenascins C, R, (X, N)R-HSA-2681681 (Reactome)
VTN:Collagen type I,IV,VIArrowR-HSA-2465883 (Reactome)
VTN:Collagen types II,III,VArrowR-HSA-2396370 (Reactome)
VTN:Integrins

alphaVbeta1, alphaVbeta3, alphaVbeta5,

alpha2bbeta3
ArrowR-HSA-2426471 (Reactome)
VTNR-HSA-2396079 (Reactome)
VTNR-HSA-2396370 (Reactome)
VTNR-HSA-2426471 (Reactome)
VTNR-HSA-2465883 (Reactome)
Vitronectin:Plasminogen activator inhibitor 1ArrowR-HSA-2396079 (Reactome)
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