Extracellular matrix organization (Homo sapiens)
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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.
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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type I
fibril:SPARC:Hydroxylapatitie:Ca2+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).
III, IV, V, XI
fibrilsnetworks:Collagen
type VII fibriltype I, II, III,
IV, V, XI fibrilstype I, II, III, V,
X fibrilsextracellular
matrixFibrillin 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).
Fibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB
homodimerFibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB
homodimeralpha3beta1,
alpha6beta4:Laminins-332, 511, 521, (211, 221)alpha3beta1,
alpha6beta4alpha5beta1:FN1
dimeralpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,
alphaVbeta1:Laminin-111alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,
alphaVbeta1alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,
alphaXbeta1surface
interactionsIntegrins 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.
alphaVbeta1, alphaVbeta3, alphaVbeta5,
alpha2bbeta3with gamma-1,
gamma-3:Nidogens:Collagen type IV networkwith gamma-1,
gamma-3:Nidogens:HSPG2alpha-1, -2 or
-5:HSPG2(22-4391)gamma-1, gamma-3:Nidogens
1,2alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,
alphaXbeta1N):Fibronectin
matrixalphaVbeta1, alphaVbeta3, alphaVbeta5,
alpha2bbeta3Annotated Interactions
type I
fibril:SPARC:Hydroxylapatitie:Ca2+III, IV, V, XI
fibrilsnetworks:Collagen
type VII fibriltype I, II, III,
IV, V, XI fibrilstype I, II, III, V,
X fibrilsFibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB
homodimerFibronectn matrix, Transthyretin tetramer, PDGFA homodimer, PDGFB
homodimeralpha3beta1,
alpha6beta4:Laminins-332, 511, 521, (211, 221)alpha3beta1,
alpha6beta4alpha5beta1:FN1
dimeralpha5beta1:FN1
dimeralpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,
alphaVbeta1:Laminin-111alpha6beta1, alpha7beta1, alpha1beta1, alpha2beta1,
alphaVbeta1alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,
alphaXbeta1alphaVbeta1, alphaVbeta3, alphaVbeta5,
alpha2bbeta3with gamma-1,
gamma-3:Nidogens:Collagen type IV networkwith gamma-1,
gamma-3:Nidogens:HSPG2alpha-1, -2 or
-5:HSPG2(22-4391)gamma-1, gamma-3:Nidogens
1,2gamma-1, gamma-3:Nidogens
1,2gamma-1, gamma-3:Nidogens
1,2Tenacious 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.
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.
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
alphaVbeta3, alphaVbeta6, alpha2beta1, alpha7beta1, alpha8beta1, alpha9beta1,
alphaXbeta1N):Fibronectin
matrixalphaVbeta1, alphaVbeta3, alphaVbeta5,
alpha2bbeta3