THIRTY YEARS AGO, BETTY HAY ORGANIZED AN INFLUENTIAL VOLUME on the extracellular matrix (ECM)

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1 Preface THIRTY YEARS AGO, BETTY HAY ORGANIZED AN INFLUENTIAL VOLUME on the extracellular matrix (ECM) that emphasized the biological effects of the ECM on cells. 1 That timely book recognized an increasing emphasis on biology in a field that had been dominated previously by biochemical and structural analyses. It was published just prior to the beginning of the impact of molecular biology on studies of ECM proteins and, during the past 30 years, we have witnessed several major transformations in our ability to understand the biology as well as the biochemistry and structure of the ECM and its molecular constituents. Among the transformational advances that one can list are molecular biology, the use of genetically engineered mice, the sequencing of multiple genomes, progress in the genetics of ECM-based diseases, and advances in imaging of cells in culture and in intact animals. These advances have led to a much more profound understanding of the roles of ECM in biological processes. The original Hay volume served as a valuable resource for the field and was followed by a second edition 10 years later. 2 We felt that the time was ripe for an updated overview of the biology of ECM, and we agreed to take on this challenge when Richard Sever at Cold Spring Harbor Laboratory Press invited us to do so. Given the ubiquity and complexity of ECMs and the enormous advances made, this was indeed a daunting task. One cannot expect to cover, in a single volume, all that we now know about ECMs, the molecules that they contain, and the myriad effects that they have upon cellular behavior. So, although we have not attempted to assemble a complete treatise on ECMs and their constituents, we have endeavored to illustrate the manifold aspects of ECM biology. The first seven chapters review the overall composition and some of the major and best understood components of the ECM: collagens, proteoglycans, and major glycoproteins. In each case, the biochemical and structural data are linked to biological functions and in many cases to human diseases. The first chapter gives an overview of the diversity of ECM proteins as revealed by genomic analyses, which provides a reasonably complete picture of the universe of ECM proteins. Basement membranes and their constituents (laminins, type IV collagen, nidogens, and perlecan) are reviewed by Yurchenco with emphasis on assembly of basement membranes, a key form of ECM universal to all metazoa. Ricard-Blum discusses the many forms of collagen and their assembly into a variety of fibrils. Both chapters discuss the cellular receptors that interact with these forms of ECM. Sarrazin et al. review the important functions of heparan sulfate proteoglycans and their interactions with soluble factors and with cell-surface receptors. The following three chapters cover three of the most intensively studied ECM glycoprotein families: thrombospondins (Adams and Lawler), tenascins (Chiquet-Ehrismann and Tucker), and fibronectins (Schwarzbauer and DeSimone). Each of these families of glycoproteins has particular biologically interesting features that collectively illustrate very well the diversity of ECM functions across almost all of biology. Implicit in the concept that the ECM helps to regulate cellular behavior is a requirement for cellular receptors to receive, interpret, and transmit the inputs. At the time of the first Hay volume, we did not have any idea how cells recognize ECM, and it was not until the mid-1980s that the molecular nature of ECM receptors became clear. The most prominent ECM receptors are integrins, present in 1 Hay ED, ed Cell biology of extracellular matrix. Plenum, New York. 2 Hay ED, ed Cell biology of extracellular matrix, 2nd ed. Plenum, New York. vii

2 Preface all metazoa and on virtually all cells. These are complex receptors, transmitting signals both into and out of cells and mediating the effects of ECM on cells and vice versa, so we have included a series of chapters covering their properties. Integrin structure and activation are reviewed by Campbell and Humphries, their ability to activate TGF-b through interactions with fibrillins and the latent TGF-b binding proteins in the ECM are covered by Munger and Sheppard, and their roles in assembling complex intracellular protein complexes with both structural and signal transduction functions are discussed by Geiger and Yamada. Wickström et al. illustrate the insights that can be gained from studies in mutant animals and contrast integrin connections to the actin-based cytoskeleton with those to intermediate filaments. These chapters lay the ground for considering the roles of integrin ECM interactions involved in mechanotransduction (Schwartz) and in cell migration (Huttenlocher and Horwitz). One of the prime reasons for interest in ECM proteins and their receptors comes from their roles in diverse biological processes, and the last third of this volume comprises a set of chapters addressing some of these processes and the involvement of the ECM. Matrix structure is not static; it is, in fact, very dynamic and the remodeling of the ECM plays an important role in development, physiology, and pathology (Lu et al. and Brown). Specific biological contexts in which ECM functions are particularly important are illustrated by angiogenesis (Senger and Davis), the nervous system (Barros et al.), normal and diseased skin (Watt and Fujiwara), and hemostasis and thrombosis (Bergmeier and Hynes). Each of these chapters illustrates different aspects of ECM functions. Collectively, these chapters encompass the diverse roles of ECM proteins, their effects on cells, and their importance in human diseases. Our increased understanding of the details of ECM structure and function coming from biochemistry; cellular, molecular, and structural biology; genetics; and genomics has confirmed their importance in the behavior of virtually all cells. Even erythrocytes, arguably the prototypical nonadherent cell type, have key interactions with the ECM during their development. It has become clear that cell ECM interactions and receptors are at least as important as those between soluble ligands (hormones, growth factors, cytokines) and their receptors. Indeed, many so-called soluble ligands actually function as ECM-bound solid-phase ligands, and many of them are completely dependent on concomitant input from ECM adhesion receptors. The central roles in development of the ECM suggested long ago by embryologists such as Clifford Grobstein have been amply confirmed, and there are preliminary indications that fundamental aspects of development and homeostasis, such as morphogen gradients and stem cell niches, rely on ECM involvement. Many human diseases arise from mutations in genes encoding ECM proteins as recognized by Victor McKusick, and cell-matrix adhesion and signaling are also affected in many autoimmune diseases. These important and fascinating topics are increasingly understood as we uncover the details of cell ECM interactions and their perturbations in disease. Drugs targeting ECM interactions are already in use in the clinic for many diseases, and it is evident that many other potential therapies will emerge from ongoing research. We hope that this collection of reviews by experts in the field will serve to promote research leading to discoveries and applications based on improved understanding of the roles of the ECM constituents, their interactions, and their receptors. RICHARD O. HYNES KENNETH M. YAMADA July 2011 viii

3 A Actin, integrin interactions cytoskeletal linkage, , mechanotransduction, non-rgd binding integrins, overview, 228 RGD motif, ADAMs collagen processing, 57 extracellular matrix modification, 10 ADAMTS collagen synthesis role, 53 extracellular matrix modification, 10, regulation, types and substrates, von Willebrand factor processing, Adhesions. See also Integrins adhesome, 207 assembly and remodeling dynamics, 214 early adhesions and molecular clutch, fibrillar adhesions, force in development of focal adhesions, 212 cell migration role assembly mechanisms and regulation, disassembly and retraction of rear, disassembly and turnover during migration, focal adhesions, 261, 264 formation variations, 267 protrusions and turnover, structures, cell extracellular matrix communication diseases adhesion-strengthening diseases, 236 integrin activation diseases, overview, classification, extracellular matrix sensing via integrin adhesions chemical sensing, 214 overview, physical sensing, , 248, functional molecular architecture, 210 integrin-mediated adhesions, molecular diversity, nonintegrin extracellular matrix receptors, 207 prospects for study, 216 regulation, scaffolding, tenascin modulation, three-dimensional environments, 205 AER. See Apical ectodermal ridge Agrin. See also Heparan sulfate proteoglycans linkage to cell surface, 26 mutant phenotypes, 70 neuromuscular junction function, Angiogenesis embryonic vasculogenesis versus adult angiogenesis integrins, 321, 324 knockout mouse phenotypes, overview, extracellular matrix role endothelial cell proliferation, survival, and migration, lumen formation, 317, 319 vascular cord formation, overview, remodeling of extracellular matrix during vascular tube formation and stabilization MT1-MMP and formation of vascular guidance tunnels, pericyte recruitment and vascular basement membrane assembly within vascular guidance tunnels, thrombospondin function in endothelial cells, 110 Apical ectodermal ridge (AER), ApoER2, 336 Arp2/3, Aspirin, 383 Axon. See Neuron B Basement membrane brain development, 33 epidermal-dermal junction, glomerular development and filtration, morphogenesis, nephronectin, 28 netrins, 28 papilin, 29 pericyte recruitment and vascular basement membrane assembly within vascular guidance tunnels,

4 Basement membrane (Continued) peripheral nerve axonal envelopment and myelination, prospects for study, sarcolemma stabilization, 32 self-assembly and receptor interactions agrin linkage to cell surface, 26 assembly steps, 24 collagen scaffolds, dystroglycan interactions, 23, 25 integrin interactions, 21, 23 laminins functional overview, nidogen complex and linkage to type IV collagen, polymerization and LN domain binding, 25 perlecan linkage to cell surface, 26 proteoglycans and growth factor tethering, 27 stromal interface collagens, solid-phase agonist activity, 29 supramolecular architecture, 18 usherin, 28 vasculature, Betaglycan, mutant phenotypes, 69 BMPs. See Bone morphogenetic proteins Bone morphogenetic proteins (BMPs) angiogenesis role, BMP-1 and collagen synthesis role, 53 extracellular matrix binding, 8, 27 fibrillin interactions, 190 Brain basement membranes in development, 33 central synapse function chondroitin sulfate proteoglycans, 344 neuronal pentaxins, 345 reelin, thrombospondins, 345 Btbd7, branching morphogenesis role, 157 C Calcium, integrin binding, Calreticulin, 109 Cancer extracellular matrix dynamics in initiation/ progression, integrin a6b4 role, skin cancer, extracellular matrix, and integrins, tenascins in invasion and metastasis, thrombospondin studies in mouser models, wound healing similarity, 366 Cas, 266, 268 CD36, CD44, 4, 11, 207 CD47, 109, 111 Cdc42, 246 Cell fate integrin extracellular matrix interaction regulation of epidermal stem cell fate, specification by extracellular matrix, Cell migration cancer invasion. See Cancer developmental functions of extracellular matrix, endothelial cell, integrin modulation adhesions assembly mechanisms and regulation, disassembly and retraction of rear, disassembly and turnover during migration, focal adhesions, 261, 264 formation variations, 267 protrusions and turnover, structures, binding specificity, 260 invadopodia, 261, podosome, polarity, signaling, 263 traction, modes, neuron. See Neuron tenascin modulation, Chondrocyte, thrombospondin function, 111 Chondroitin sulfate proteoglycans (CSPGs) axonal growth and myelination regulation, 339 central synapse function, 344 Clopidogrel, 383 Collagens assembly fibril-associated collagens, 52 fibril-forming collagens, network-forming collagens, basement membrane-stromal interface collagens, biosynthesis, 53 collagen-like domains in proteins, 47 cross-linking, degradation, 56 diseases, hemostasis role, 378 matricryptins, 57 neuromuscular junction function, 344 receptors, 55 structure domains, overview,

5 trimerization domains, 51 triple helix, 48 superfamily, type I structure, 3 vascular cord formation, type IV collagen in basement membrane laminin-nidogen complex binding, stabilization, supramolecular architecture, type VI function, 28 type VII function, 56 type XIII function, type XV function, 28 type XVIII. See also Heparan sulfate proteoglycans, 70 function, 27 28, 66 mutant phenotypes, 70, 84 type XXIV function, 56 type XXVII function, 52, 56 COMP. See Thrombospondins Connective tissue growth factor (CTGF), fibrosis role, 364 Crk, adhesion regulation, 2 CSPGs. See Chondroitin sulfate proteoglycans CTGF. See Connective tissue growth factor Cytochalasin D, 212 Cytoskeleton. See Actin D DDD motif, 107 DDR. See Discoidin domain receptor Dermal papilla (DP), 362 Development basement membrane early morphogenesis, brain basement membranes, 33 composition changes in extracellular matrix, 302 defining of extracellular matrix, diffusion in extracellular matrix formation, epithelial branch patterning and extracellular matrix dynamics, 287 extracellular matrix functions cell fate specification, cell migration, glue, insulation, overview, signaling modulation, structural roles, 308 fibril developmental mechanisms and consequences of assembly, glomerular development and filtration, heparan sulfate proteoglycans and gradient creation for morphogens, receptors in extracellular matrix assembly, 301 skeletal development and extracellular matrix dynamics, stem cell differentiation, vasculogenesis versus adult angiogenesis integrins, 321, 324 knockout mouse phenotypes, overview, Dimensionality, extracellular matrix, 203 Discoidin domain receptor (DDR) adhesions, 207 collagen binding, 55 ligands, 11 DOCK180, 250 DP. See Dermal papilla Dystroglycan, 11, 23, 25, 337 E EB. See Epidermolysis bullosa EC. See Endothelial cell EDA. See Extra domain A EGF. See Epidermal growth factor EHS sarcoma. See Engelbreth-Holm-Swarm sarcoma Elasticity, extracellular matrix, 203, EMT. See Epithelial mesenchymal transition Ena, 251 Endothelial cell (EC). See also Angiogenesis extracellular matrix role in proliferation, survival, and migration, thrombospondin function, 110 vascular endothelium, 372 Engelbreth-Holm-Swarm (EHS) sarcoma, 1 Epidermal growth factor (EGF), integrin domain, Epidermolysis bullosa (EB), 236, 238 Epithelial mesenchymal transition (EMT), 215, 252 Extra domain A (EDA), 230 Extra type domains, , 381 F Factor XIII, 382 FAK. See Focal adhesion kinase FERMT. See Kindlins FGFs. See Fibroblast growth factors Fibrillins latent transforming growth factor-b homology, 187 interactions, structure, assembly, Fibrillogenesis. See Fibronectins Fibrin, cellular interactions with clot, 382 Fibroblast growth factors (FGFs) angiogenesis role,

6 Fibroblast growth factors (FGFs) (Continued) extracellular matrix binding, 27, 285 heparan sulfate proteoglycan binding, skeletal development and remodeling, 288 Fibronectins adhesions, , assembly of fibrils deoxycholate insolubility, 9, developmental mechanisms and consequences of assembly, monomer monomer interactions, 154 overview, receptor requirements and intracellular connections, deoxycholate insolubility, 9, domain organization and isoforms, modules, phylogeny, prospects for study, splice variants, Focal adhesion. See Adhesions Focal adhesion kinase (FAK) activation by force, 248 adhesion turnover modulation in protrusions, 268 fibrillogenesis role, 155 mechanotransduction, 214, 253 phosphorylation, 252 Force, cellular responses, F-spondin, 340 G GFOGER motif, 176 Glomerulus basement membrane barrier activity, 83 development and filtration, Glycoprotein Ib-V-IX receptor complex, hemostasis role, Glycoprotein VI (GPVI) collagen binding, 56, 374, 383 hemostasis role, platelet adhesion, 374 Glypicans. See also Heparan sulfate proteoglycans morphogen gradient formation, 84 mutant phenotypes, GPVI. See Glycoprotein VI Hemidesmisome assembly, epidermal integrity role, integrin a6b4 in cancer, structure, Hemostasis/thrombosis collagens, 378 fibrin clot retraction and wound healing, 382 glycoprotein Ib-V-IX receptor complex, glycoprotein VI, , 381, 383 integrins a2b1 integrin, 379 aiibb3 integrin, 377 laminins, platelet aggregation, extracellular matrix interactions in adhesion, relative contributions of receptors and extracellular matrix components to thrombosis and hemostasis, vascular structure, von Willebrand factor, Heparan sulfate proteoglycans (HSPGs). See also specific proteoglycans adhesion receptor activity, barrier activity, 83 coreceptor function, endocytic receptor activity, functional overview, 65 67, 73 gradient creation for morphogens and chemokines, growth factor binding to extracellular matrix mediation, 82 ligand binding sites, specificity, mutant phenotypes, stem cell niche, structure and assembly, Hepatocyte growth factor (HGF), angiogenesis role, HGF. See Hepatocyte growth factor Hh. See Hedgehog HSP47. See Heat shock protein-47 HSPGs. See Heparan sulfate proteoglycans Hyl211, 53 H Heat shock protein-47 (HSP47), collagen synthesis role, 53 Hedgehog (Hh) heparan sulfate proteoglycans in gradient formation, 84, 306 sonic hedgehog, 362 I ILK. See Integrin-linked kinase Inc5, 341 Integrin-linked kinase (ILK), 231, Integrins. See also Adhesions actin interactions cytoskeletal linkage, ,

7 non-rgd binding integrins, overview, 228 RGD motif, activation antagonists, conformational regulation, aging effects on skin, 363 basement membrane interactions, 21, 23 cell migration role adhesions assembly mechanisms and regulation, disassembly and retraction of rear, disassembly and turnover during migration, focal adhesions, 261, 264 formation variations, 267 protrusions and turnover, structures, binding specificity, 260 invadopodia, 261, podosome, polarity, signaling, 263 traction, diseases of cell extracellular matrix interaction adhesion-strengthening diseases, 236 integrin activation diseases, embryonic vasculogenesis versus adult angiogenesis, 321, 324 epidermal stem cell extracellular matrix interaction regulation of stem cell fate, markers, 360 fibrillogenesis role, fibrosis role, 364 hemidesmisome assembly, epidermal integrity role, integrin a6b4 in cancer, structure, hemostasis role a2b1 integrin, 379 aiibb3 integrin, 377 Integrins ligands binding, cytoplasmic tail ligands, 174 prospects for study, 179 signaling inside-out signaling and consequences of loss, kindlins, mechanotransduction, , outside-in signaling and consequences of loss, talin, 231, 233 skin cancer role, structure a-subunit ectodomains, 171 b-subunit ectodomains, cation-binding sites, 172 cytoplasmic tail, 174 ectodomains, 170 intact integrin studies, overview, transmembrane segments, syndecan-1 interactions, 76, 81 thrombospondin interactions, transforming growth factor-b activation by integrins avb5 integrin, RGD-binding integrins, redundancy among growth factor isoforms and integrin activators, signaling cross talk, , Intermediate filament. See Hemidesmisome Invadopodia, 261, IPP complex, 231, J Jagged, 109 K Kindlins, integrin signaling, Knobloch syndrome, 28 L LAD. See Leukocyte adhesion deficiency LAIR. See Leukocyte-associated immunoglobulin-like receptor Laminins axonal growth and myelination regulation, 337, 339 basement membrane functional overview, nidogen complex and linkage to type IV collagen, polymerization and LN domain binding, 25 supramolecular architecture, 18 cytokine presentation, deficiency and neurological disease, hemostasis role, integrin interactions, 224 laminin-1 signaling in endothelial cells, neural stem cell behavior and neuronal migration role, neuromuscular junction function, subunits, 20 types,

8 Latent transforming growth factor-b binding protein (LTBP). See Transforming growth factor-b LDS. See Loews-Dietz syndrome Leukocyte adhesion deficiency (LAD), Leukocyte-associated immunoglobulin-like receptor (LAIR), collagen binding, 56 LG domain, 19, 23, 26, 32 33, LN domain, 25, 32 Loews-Dietz syndrome (LDS), 191 Long-term potentiation (LTP), 345 LOX. See Lysyl oxidase LRP1, 106 LTBP. See Latent transforming growth factor-b binding protein LTP. See Long-term potentiation Lysyl oxidase (LOX), 280 M Mac-1, 382 Magnesium, integrin binding, 172 MAL, 361 MAPK. See Mitogen-activated protein kinase Marfan syndrome (MFS) clinical features, 190 transforming growth factor-b role, Matrisome cellular receptors, definition, 2 evolution, modifiers of structure and function, 9 10 overview of components collagens, 3 4 glycoproteins, 5 8 growth factors, 8 9 proteoglycans, 4 5 protein databases, 2 Matrix metalloproteinases (MMPs) collagen degradation, 56 epithelial branch patterning during organogenesis, 287 extracellular matrix modification, 10, 19, MT1-MMP and formation of vascular guidance tunnels, regulation, skeletal development and remodeling, syndecan shedding mediation, 79 tissue inhibitors, 282 types and substrates, MATRIXOME, 359 Mechanical properties, extracellular matrix, 203 Met93, 53 MFS. See Marfan syndrome Migration. See Cell migration Mitogen-activated protein kinase (MAPK) adhesion modulation, 134 adhesion signaling, 214 endothelial cell proliferation, survival, and migration, 315 stem cell fate regulation, 361 tenascin signaling, vascular cord formation, 317 MLCK. See Myosin light chain kinase MMPs. See Matrix metalloproteinases MT1-MMP. See Matrix metalloproteinases Muscular dystrophy congenital, 337, 339 gene mutations, Myc, regulation of integrin expression, Myelination. See Neuron Myoblast, thrombospondin function, 111 Myosin light chain kinase (MLCK), 269 N Neogenin, 341 Nephronectin, basement membrane function, 28 Netrins axonal growth and myelination regulation, basement membrane function, 28 Neuromuscular junction (NMJ) extracellular matrix function agrin, collagens, 344 laminins, overview, 342 Neuron axonal growth and myelination regulation laminins, 337, 339 netrins, proteoglycans, 339 slits, tenascins, thrombospondins, 340 central synapse function chondroitin sulfate proteoglycans, 344 neuronal pentaxins, 345 reelin, thrombospondins, 345 neural stem cell behavior and neuronal migration extracellular matrix function laminins, proteoglycans, reelin, tenascins, 336 overview, peripheral nerve axonal envelopment and myelination, thrombospondin function,

9 Nidogen, laminin complex and linkage to type IV collagen, Nitric oxide (NO), thrombospondin and signaling antagonism, NMJ. See Neuromuscular junction NO. See Nitric oxide Noggin, 362 Notch, 109 O Oligodendrocyte precursor cell (OPC), 340 OPC. See Oligodendrocyte precursor cell Osteoblast, thrombospondin function, 111 P PAK, 268 Papilin, basement membrane function, 29 PCP. See Planar cell polarity PDGF. See Platelet-derived growth factor Pericyte, recruitment and vascular basement membrane assembly within vascular guidance tunnels, Perlecan. See also Heparan sulfate proteoglycans linkage to cell surface, 26 mutant phenotypes, 69 Planar cell polarity (PCP), Plasmin, extracellular matrix degradation, 277 Platelet aggregation, extracellular matrix interactions in adhesion, relative contributions of receptors and extracellular matrix components to thrombosis and hemostasis, Platelet-derived growth factor (PDGF) extracellular matrix binding, 27, 82 fibril association, 157 fibrosis role, 364 Podosome, Proteoglycans. See also specific proteoglycans classification, 4 5 growth factor tethering, 27 PSACH. See Pseudoachondroplasia Pseudoachondroplasia (PSACH), thrombospondin defects, 115 PTB domain, 174 Pyrogenic sterile arthritis, pyoderma, gangrenosum, and acne (PAPA), 265 R Rab5, 80 Rac, 246, 268, 317 Radial glial cell (RGC), , 336 RE1 Silencing Factor (REST), Reelin central synapse function, neural stem cell behavior and neuronal migration role, phylogeny, REST. See RE1 Silencing Factor RGC. See Radial glial cell RGD motif, 107, 131, 153, , , , 249, 336 RHAMM, 207 Rho adhesion regulation, 209, fibrillogenesis role, 155 force signaling, 250 vascular cord formation role, 317 RIAM, 263 Rigidity, extracellular matrix overview, 203 remodeling effects, 283 spread area, ROCK, 70 S Sarcolemma, stabilization, 32 SCO-spondin, 340 Serglycin, mutant phenotypes, 69 Skin aging effects, 363 cancer extracellular matrix, wound healing similarity, 366 epidermal stem cell integrin extracellular matrix interaction regulation of stem cell fate, markers, epidermal dermal junction, extracellular matrix heterogeneity, 359 prospects for study, 366 fibrosis, 364, 366 hemidesmisomes and epidermal integrity role, hyperproliferation and wound healing, non-cell autonomous functions of epidermal integrins and extracellular matrix, 362 structure, Slits, axonal growth and myelination regulation, Smooth muscle cell thrombospondin in migration and proliferation, 110 vasculature, 372 Squamous cell carcinoma. See Skin Src adhesion turnover role, 268 vascular cord formation role,

10 SRF, 361 SSS. See Stiff skin syndrome Stem cell differentiation and extracellular matrix dynamics, epidermal stem cell integrin extracellular matrix interaction regulation of stem cell fate, markers, heparan sulfate proteoglycans in niche, neural stem cell. See Neuron Stiff skin syndrome (SSS), 187, 191 Syndecans. See also Heparan sulfate proteoglycans coreceptor activity, development role, 82 fibrillogenesis role, 155 integrin interactions, 76, 81 mutant phenotypes, T Talin, integrin signaling, 231, 233 Tat, 80 Tenascins axonal growth and myelination regulation, cancer invasion and metastasis role, cell adhesion modulation, evolution, 13 14, expression regulation, knockout mouse phenotypes, neural stem cell behavior and neuronal migration role, 336 tenascin-c discovery, types, 130 TGF-b. See Transforming growth factor-b Thrombosis. See Hemostasis/thrombosis Thrombospondins (TSPs) axonal growth and myelination regulation, 340 binding partners, central synapse function, 345 degradation, domains architecture, structure, evolution, functions cell studies chondrocyte, 111 endothelial cell, 110 myoblast, 111 neuron, 111 nitric oxide signaling antagonism, osteoblast, 111 smooth muscle cell migration and proliferation, 110 Drosophila studies, 112 human disease, mouse studies cancer models, knockout mice, prospects for study, 116 single nucleotide polymorphisms, 115 synthesis, 103, 105 tissue expression patterns, TSP-5/COMP oligomerization domain, Tie-2, 320 Tissue plasminogen activator (tpa), 282, 382 tpa. See Tissue plasminogen activator Transforming growth factor-b (TGF-b) activation activator types, 193 integrin avb5, modes, 195 overview, redundancy among growth factor isoforms and integrin activators, RGD-binding integrins, diseases, extracellular matrix binding, 8, 27 fibrosis role, 364 force effects on processing, 251 integrin cross talk, , isoforms, 184 knockout mouse phenotypes, , 194 latent transforming growth factor-b binding protein fibrillins homology, 187 interactions, functional overview, mutations, structure, prospects for study, 195 thrombospondin interactions, TSPs. See Thrombospondins U upa. See Urokinase plasminogen activator Urokinase plasminogen activator (upa), 282 Usherin, basement membrane function, 28 V Vascular cord. See Angiogenesis Vascular endothelial growth factor (VEGF). See also Angiogenesis; Vasculogenesis angiogenesis role, extracellular matrix binding, 27 heparan sulfate proteoglycan coreceptor, 79 thrombospondin interactions,

11 Vasculogenesis, adult angiogenesis comparison integrins, 321, 324 knockout mouse phenotypes, overview, VASP, 251 VEGF. See Vascular endothelial growth factor Versican, 339 VLDLR, 336 von Willebrand factor (VWF) hemostasis role, processing, structure, 374 VWF. See von Willebrand factor W WASP, 265 Wnt, fibrillogenesis regulation in development, Wound healing cancer similarity, 366 epidermal hyperproliferation, fibrin clot cellular interactions, 382 Z Zyxin, force signaling,

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