i-viii cshperspect-ecm-fm 1. · some of these processesand the involvement of the ecm. matrix...

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 andstructural analyses. It was published just prior to the beginning of the impact of molecularbiology on studies of ECM proteins and, during the past 30 years, we have witnessed severalmajor transformations in our ability to understand the biology as well as the biochemistry and struc-ture of the ECM and its molecular constituents. Among the transformational advances that one canlist are molecular biology, the use of genetically engineered mice, the sequencing of multiplegenomes, progress in the genetics of ECM-based diseases, and advances in imaging of cells inculture and in intact animals. These advances have led to a much more profound understandingof the roles of ECM in biological processes.

The original Hay volume served as a valuable resource for the field and was followed by a secondedition 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 LaboratoryPress invited us to do so. Given the ubiquity and complexity of ECMs and the enormous advancesmade, this was indeed a daunting task. One cannot expect to cover, in a single volume, all that we nowknow about ECMs, the molecules that they contain, and the myriad effects that they have upon cel-lular behavior. So, although we have not attempted to assemble a complete treatise on ECMs andtheir 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 under-stood components of the ECM: collagens, proteoglycans, and major glycoproteins. In each case, thebiochemical and structural data are linked to biological functions and in many cases to human dis-eases. The first chapter gives an overview of the diversity of ECM proteins as revealed by genomicanalyses, 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 ofECM universal to all metazoa. Ricard-Blum discusses the many forms of collagen and their assemblyinto a variety of fibrils. Both chapters discuss the cellular receptors that interact with these forms ofECM. Sarrazin et al. review the important functions of heparan sulfate proteoglycans and their inter-actions with soluble factors and with cell-surface receptors. The following three chapters cover threeof the most intensively studied ECM glycoprotein families: thrombospondins (Adams and Lawler),tenascins (Chiquet-Ehrismann and Tucker), and fibronectins (Schwarzbauer and DeSimone). Eachof these families of glycoproteins has particular biologically interesting features that collectively illus-trate 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 cel-lular receptors to receive, interpret, and transmit the inputs. At the time of the first Hay volume, wedid not have any idea how cells recognize ECM, and it was not until the mid-1980s that the molecularnature of ECM receptors became clear. The most prominent ECM receptors are integrins, present in

1Hay ED, ed. 1981. Cell biology of extracellular matrix. Plenum, New York.2Hay ED, ed. 1991. Cell biology of extracellular matrix, 2nd ed. Plenum, New York.

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all metazoa and on virtually all cells. These are complex receptors, transmitting signals both into andout of cells and mediating the effects of ECM on cells and vice versa, so we have included a series ofchapters covering their properties. Integrin structure and activation are reviewed by Campbell andHumphries, their ability to activate TGF-b through interactions with fibrillins and the latentTGF-b binding proteins in the ECM are covered by Munger and Sheppard, and their roles in assem-bling complex intracellular protein complexes with both structural and signal transduction functionsare discussed by Geiger and Yamada. Wickstrom et al. illustrate the insights that can be gained fromstudies in mutant animals and contrast integrin connections to the actin-based cytoskeleton withthose to intermediate filaments. These chapters lay the ground for considering the roles of inte-grin–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 rolesin diverse biological processes, and the last third of this volume comprises a set of chapters addressingsome 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 par-ticularly important are illustrated by angiogenesis (Senger and Davis), the nervous system (Barroset al.), normal and diseased skin (Watt and Fujiwara), and hemostasis and thrombosis (Bergmeierand 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 struc-ture 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 theirdevelopment. It has become clear that cell–ECM interactions and receptors are at least as importantas 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 ofthem are completely dependent on concomitant input from ECM adhesion receptors. The centralroles in development of the ECM suggested long ago by embryologists such as Clifford Grobsteinhave been amply confirmed, and there are preliminary indications that fundamental aspects of devel-opment and homeostasis, such as morphogen gradients and stem cell niches, rely on ECM involve-ment. Many human diseases arise from mutations in genes encoding ECM proteins as recognized byVictor McKusick, and cell-matrix adhesion and signaling are also affected in many autoimmune dis-eases. These important and fascinating topics are increasingly understood as we uncover the detailsof cell–ECM interactions and their perturbations in disease. Drugs targeting ECM interactions arealready in use in the clinic for many diseases, and it is evident that many other potential therapies willemerge from ongoing research. We hope that this collection of reviews by experts in the field will serveto promote research leading to discoveries and applications based on improved understanding of theroles of the ECM constituents, their interactions, and their receptors.

RICHARD O. HYNES

KENNETH M. YAMADA

July 2011

Preface

viii


Index

AActin, integrin interactions

cytoskeletal linkage, 230–231, 246–247mechanotransduction, 249–250non-RGD binding integrins, 229–230overview, 228RGD motif, 228–229

ADAMscollagen processing, 57extracellular matrix modification, 10

ADAMTScollagen synthesis role, 53

extracellular matrix modification, 10, 276–277regulation, 281–282types and substrates, 279–280von Willebrand factor processing, 374–375

Adhesions. See also Integrins

adhesome, 207assembly and remodeling

dynamics, 214early adhesions and molecular clutch, 211–212

fibrillar adhesions, 213–214force in development of focal adhesions, 212

cell migration roleassembly mechanisms and regulation, 265–267disassembly and retraction of rear, 269–270

disassembly and turnover during migration,267–270

focal adhesions, 261, 264formation variations, 267protrusions and turnover, 267–268

structures, 263–264cell–extracellular matrix communication

diseasesadhesion-strengthening diseases, 236integrin activation diseases, 235–236

overview, 215–216classification, 204–205extracellular matrix sensing via integrin adhesions

chemical sensing, 214

overview, 213–214physical sensing, 214–215, 248, 252–253

functional molecular architecture, 210integrin-mediated adhesions, 204–205molecular diversity, 204–207

nonintegrin extracellular matrix receptors, 207prospects for study, 216

regulation, 208–210scaffolding, 207–208tenascin modulation, 132–134

three-dimensional environments, 205AER. See Apical ectodermal ridgeAgrin. See also Heparan sulfate proteoglycans

linkage to cell surface, 26mutant phenotypes, 70

neuromuscular junction function, 342–343Angiogenesis

embryonic vasculogenesis versus adult angiogenesisintegrins, 321, 324knockout mouse phenotypes, 322–323

overview, 320–321extracellular matrix role

endothelial cell proliferation, survival, andmigration, 315–316

lumen formation, 317, 319vascular cord formation, 316–317

overview, 314–315remodeling of extracellular matrix during vascular

tube formation and stabilization

MT1-MMP and formation of vascular guidancetunnels, 325–326

pericyte recruitment and vascular basementmembrane assembly within vascularguidance tunnels, 326–327

thrombospondin function in endothelial cells, 110Apical ectodermal ridge (AER), 287–288ApoER2, 336Arp2/3, 266–267Aspirin, 383

Axon. See Neuron

BBasement membrane

brain development, 33epidermal-dermal junction, 31–32glomerular development and filtration, 30–31morphogenesis, 29–30

nephronectin, 28netrins, 28papilin, 29pericyte recruitment and vascular basement

membrane assembly within vascular

guidance tunnels, 326–327

389


Basement membrane (Continued)peripheral nerve axonal envelopment

and myelination, 32–33prospects for study, 34–35

sarcolemma stabilization, 32self-assembly and receptor interactions

agrin linkage to cell surface, 26assembly steps, 24collagen scaffolds, 18–19

dystroglycan interactions, 23, 25integrin interactions, 21, 23laminins

functional overview, 19–21nidogen complex and linkage to type IV

collagen, 25–26polymerization and LN domain

binding, 25perlecan linkage to cell surface, 26

proteoglycans and growth factor tethering, 27stromal interface collagens, 27–28

solid-phase agonist activity, 29supramolecular architecture, 18usherin, 28

vasculature, 33–34Betaglycan, mutant phenotypes, 69BMPs. See Bone morphogenetic proteinsBone morphogenetic proteins (BMPs)

angiogenesis role, 319–320

BMP-1 and collagen synthesis role, 53extracellular matrix binding, 8, 27fibrillin interactions, 190

Brainbasement membranes in development, 33

central synapse functionchondroitin sulfate proteoglycans, 344neuronal pentaxins, 345reelin, 344–345

thrombospondins, 345Btbd7, branching morphogenesis role, 157

CCalcium, integrin binding, 171–172Calreticulin, 109Cancer

extracellular matrix dynamics in initiation/progression, 291–294

integrin a6b4 role, 227–228skin cancer, extracellular matrix, and integrins,

364–366tenascins in invasion and metastasis, 136–138

thrombospondin studies in mouser models,114–115

wound healing similarity, 366Cas, 266, 268CD36, 109–111

CD44, 4, 11, 207CD47, 109, 111Cdc42, 246Cell fate

integrin–extracellular matrix interaction regulationof epidermal stem cell fate, 361–362

specification by extracellular matrix, 304–305Cell migration

cancer invasion. See Cancer

developmental functions of extracellular matrix,302–304

endothelial cell, 315–316integrin modulation

adhesions

assembly mechanisms and regulation,265–267

disassembly and retraction of rear, 269–270disassembly and turnover during migration,

267–270focal adhesions, 261, 264formation variations, 267protrusions and turnover, 267–268structures, 263–264

binding specificity, 260invadopodia, 261, 264–265podosome, 264–265polarity, 261–262signaling, 263

traction, 261–263modes, 259–260neuron. See Neurontenascin modulation, 136–138

Chondrocyte, thrombospondin function, 111

Chondroitin sulfate proteoglycans (CSPGs)axonal growth and myelination regulation, 339central synapse function, 344

Clopidogrel, 383

Collagensassembly

fibril-associated collagens, 52fibril-forming collagens, 51–52network-forming collagens, 52–53

basement membrane-stromal interface collagens,27–28

biosynthesis, 53collagen-like domains in proteins, 47cross-linking, 53–56

degradation, 56diseases, 58–59hemostasis role, 378matricryptins, 57neuromuscular junction function, 344

receptors, 55structure

domains, 48–51overview, 3–4

Index

390


trimerization domains, 51triple helix, 48

superfamily, 45–48type I

structure, 3vascular cord formation, 316–318

type IV collagen in basement membranelaminin-nidogen complex binding, 25–26stabilization, 26–27

supramolecular architecture, 18–19type VI function, 28type VII function, 56type XIII function, 56–57type XV function, 28

type XVIII. See also Heparan sulfateproteoglycans, 70

function, 27–28, 66mutant phenotypes, 70, 84

type XXIV function, 56type XXVII function, 52, 56

COMP. See ThrombospondinsConnective tissue growth factor (CTGF), fibrosis role,

364

Crk, adhesion regulation, 2CSPGs. See Chondroitin sulfate proteoglycansCTGF. See Connective tissue growth factorCytochalasin D, 212Cytoskeleton. See Actin

DDDD motif, 107

DDR. See Discoidin domain receptorDermal papilla (DP), 362Development

basement membrane early morphogenesis, 29–30brain basement membranes, 33

composition changes in extracellular matrix, 302defining of extracellular matrix, 299–300diffusion in extracellular matrix formation,

300–301epithelial branch patterning and extracellular matrix

dynamics, 287extracellular matrix functions

cell fate specification, 304–305cell migration, 302–304glue, 306–308

insulation, 306–308overview, 302–303signaling modulation, 305–306structural roles, 308

fibril developmental mechanisms and consequencesof assembly, 156–160

glomerular development and filtration, 30–31heparan sulfate proteoglycans and gradient creation

for morphogens, 83–84

receptors in extracellular matrix assembly, 301skeletal development and extracellular matrix

dynamics, 287–290stem cell differentiation, 290–291

vasculogenesis versus adult angiogenesisintegrins, 321, 324knockout mouse phenotypes, 322–323overview, 320–321

Dimensionality, extracellular matrix, 203

Discoidin domain receptor (DDR)adhesions, 207collagen binding, 55ligands, 11

DOCK180, 250

DP. See Dermal papillaDystroglycan, 11, 23, 25, 337

EEB. See Epidermolysis bullosaEC. See Endothelial cellEDA. See Extra domain AEGF. See Epidermal growth factorEHS sarcoma. See Engelbreth-Holm-Swarm sarcoma

Elasticity, extracellular matrix, 203, 285–286EMT. See Epithelial–mesenchymal transitionEna, 251Endothelial cell (EC). See also Angiogenesis

extracellular matrix role in proliferation, survival,

and migration, 315–316thrombospondin function, 110vascular endothelium, 372

Engelbreth-Holm-Swarm (EHS) sarcoma, 1Epidermal growth factor (EGF), integrin domain,

171–172Epidermolysis bullosa (EB), 236, 238Epithelial–mesenchymal transition (EMT), 215, 252Extra domain A (EDA), 230

Extra type domains, 151–152, 381

FFactor XIII, 382FAK. See Focal adhesion kinaseFERMT. See Kindlins

FGFs. See Fibroblast growth factorsFibrillins

latent transforming growth factor-bhomology, 187

interactions, 189–190structure, 187–188assembly, 188–190

Fibrillogenesis. See FibronectinsFibrin, cellular interactions with clot, 382

Fibroblast growth factors (FGFs)angiogenesis role, 320

Index

391


Fibroblast growth factors (FGFs) (Continued)extracellular matrix binding, 27, 285heparan sulfate proteoglycan binding, 76–78skeletal development and remodeling, 288

Fibronectinsadhesions, 205–206, 212–213assembly of fibrils

deoxycholate insolubility, 9, 155–156developmental mechanisms and consequences

of assembly, 156–160monomer–monomer interactions, 154overview, 153–154receptor requirements and intracellular

connections, 154–155

deoxycholate insolubility, 9, 155–156domain organization and isoforms, 150–151modules, 149–150phylogeny, 13–14

prospects for study, 160–161splice variants, 151–152

Focal adhesion. See AdhesionsFocal adhesion kinase (FAK)

activation by force, 248

adhesion turnover modulationin protrusions, 268

fibrillogenesis role, 155mechanotransduction, 214, 253phosphorylation, 252

Force, cellular responses, 247–248F-spondin, 340

GGFOGER motif, 176

Glomerulusbasement membrane barrier activity, 83development and filtration, 30–31

Glycoprotein Ib-V-IX receptor complex, hemostasis

role, 376–377Glycoprotein VI (GPVI)

collagen binding, 56, 374, 383hemostasis role, 378–379platelet adhesion, 374

Glypicans. See also Heparan sulfate proteoglycansmorphogen gradient formation, 84mutant phenotypes, 68–69

GPVI. See Glycoprotein VI

HHeat shock protein-47 (HSP47), collagen

synthesis role, 53Hedgehog (Hh)

heparan sulfate proteoglycans in gradient

formation, 84, 306sonic hedgehog, 362

Hemidesmisomeassembly, 225–226epidermal integrity role, 226–227integrin a6b4 in cancer, 227–228

structure, 224–225Hemostasis/thrombosis

collagens, 378fibrin clot retraction and wound healing, 382glycoprotein Ib-V-IX receptor complex, 376–377

glycoprotein VI, 378–379, 381, 383integrins

a2b1 integrin, 379aIIbb3 integrin, 377

laminins, 379–380

plateletaggregation, 380–381extracellular matrix interactions in adhesion,

373–374

relative contributions of receptors andextracellular matrix components tothrombosis and hemostasis, 381–382

vascular structure, 372–373von Willebrand factor, 374–377

Heparan sulfate proteoglycans (HSPGs). See also specificproteoglycans

adhesion receptor activity, 81–82barrier activity, 83coreceptor function, 77–80

endocytic receptor activity, 80–81functional overview, 65–67, 73gradient creation for morphogens and chemokines,

83–84growth factor binding to extracellular matrix

mediation, 82ligand binding

sites, 75–76specificity, 76–77

mutant phenotypes, 67–72stem cell niche, 84–85structure and assembly, 73–75

Hepatocyte growth factor (HGF), angiogenesis role,319–320

HGF. See Hepatocyte growth factorHh. See HedgehogHSP47. See Heat shock protein-47HSPGs. See Heparan sulfate proteoglycansHyl211, 53

IILK. See Integrin-linked kinase

Inc5, 341Integrin-linked kinase (ILK), 231, 233–234Integrins. See also Adhesions

actin interactionscytoskeletal linkage, 230–231, 246–247

Index

392


non-RGD binding integrins, 229–230overview, 228RGD motif, 228–229

activation

antagonists, 178–179conformational regulation, 176–178

aging effects on skin, 363basement membrane interactions, 21, 23cell migration role

adhesionsassembly mechanisms and regulation, 265–267disassembly and retraction of rear, 269–270disassembly and turnover during migration,

267–270

focal adhesions, 261, 264formation variations, 267protrusions and turnover, 267–268structures, 263–264

binding specificity, 260invadopodia, 261, 264–265podosome, 264–265polarity, 261–262signaling, 263

traction, 261–263diseases of cell–extracellular matrix interaction

adhesion-strengthening diseases, 236integrin activation diseases, 235–236

embryonic vasculogenesis versus adult angiogenesis,

321, 324epidermal stem cell

extracellular matrix interaction regulationof stem cell fate, 361–362

markers, 360

fibrillogenesis role, 154–155fibrosis role, 364hemidesmisome

assembly, 225–226

epidermal integrity role, 226–227integrin a6b4 in cancer, 227–228structure, 224–225

hemostasis rolea2b1 integrin, 379

aIIbb3 integrin, 377Integrins

ligandsbinding, 175–176cytoplasmic tail ligands, 174

prospects for study, 179signaling

inside-out signaling and consequences of loss,231–233

kindlins, 231–233

mechanotransduction, 248–249, 252–253outside-in signaling and consequences of loss,

233–234talin, 231, 233

skin cancer role, 364–366structure

a-subunit ectodomains, 171b-subunit ectodomains, 171–172

cation-binding sites, 172cytoplasmic tail, 174ectodomains, 170intact integrin studies, 174–175overview, 169–170

transmembrane segments, 172–174syndecan-1 interactions, 76, 81thrombospondin interactions, 106–107transforming growth factor-b

activation by integrins

avb5 integrin, 194–195RGD-binding integrins, 192–193

redundancy among growth factor isoformsand integrin activators, 193–194

signaling cross talk, 184–185, 192–195Intermediate filament. See HemidesmisomeInvadopodia, 261, 264–265IPP complex, 231, 233–234

JJagged, 109

KKindlins, integrin signaling, 231–233Knobloch syndrome, 28

LLAD. See Leukocyte adhesion deficiencyLAIR. See Leukocyte-associated immunoglobulin-like

receptorLaminins

axonal growth and myelination regulation, 337, 339basement membrane

functional overview, 19–21nidogen complex and linkage to type IV collagen,

25–26

polymerization and LN domain binding, 25supramolecular architecture, 18

cytokine presentation, 319–320deficiency and neurological disease, 32–33hemostasis role, 379–380

integrin interactions, 224laminin-1 signaling in endothelial cells,

317–318neural stem cell behavior and neuronal migration

role, 334–335neuromuscular junction function, 343–344subunits, 20types, 19

Index

393


Latent transforming growth factor-b binding protein(LTBP). See Transforming growthfactor-b

LDS. See Loews-Dietz syndrome

Leukocyte adhesion deficiency (LAD), 235–236Leukocyte-associated immunoglobulin-like receptor

(LAIR), collagen binding, 56LG domain, 19, 23, 26, 32–33, 108–109LN domain, 25, 32

Loews-Dietz syndrome (LDS), 191Long-term potentiation (LTP), 345LOX. See Lysyl oxidaseLRP1, 106LTBP. See Latent transforming growth factor-b binding

proteinLTP. See Long-term potentiationLysyl oxidase (LOX), 280

MMac-1, 382Magnesium, integrin binding, 172MAL, 361MAPK. See Mitogen-activated protein kinase

Marfan syndrome (MFS)clinical features, 190transforming growth factor-b role, 190–191

Matrisomecellular receptors, 10–12

definition, 2evolution, 12–14modifiers of structure and function, 9–10overview of components

collagens, 3–4

glycoproteins, 5–8growth factors, 8–9proteoglycans, 4–5

protein databases, 2

Matrix metalloproteinases (MMPs)collagen degradation, 56epithelial branch patterning during organogenesis,

287extracellular matrix modification, 10, 19,

276–277MT1-MMP and formation of vascular guidance

tunnels, 325–326regulation, 280–282skeletal development and remodeling, 288–289

syndecan shedding mediation, 79tissue inhibitors, 282types and substrates, 278–279

MATRIXOME, 359Mechanical properties, extracellular matrix, 203

Met93, 53MFS. See Marfan syndromeMigration. See Cell migration

Mitogen-activated protein kinase (MAPK)adhesion modulation, 134adhesion signaling, 214endothelial cell proliferation, survival, and

migration, 315stem cell fate regulation, 361tenascin signaling, 134–135vascular cord formation, 317

MLCK. See Myosin light chain kinase

MMPs. See Matrix metalloproteinasesMT1-MMP. See Matrix metalloproteinasesMuscular dystrophy

congenital, 337, 339gene mutations, 236–237

Myc, regulation of integrin expression, 360–361Myelination. See NeuronMyoblast, thrombospondin function, 111Myosin light chain kinase (MLCK), 269

NNeogenin, 341Nephronectin, basement membrane function, 28Netrins

axonal growth and myelination regulation,340–341

basement membrane function, 28Neuromuscular junction (NMJ)

extracellular matrix function

agrin, 342–343collagens, 344laminins, 343–344

overview, 342Neuron

axonal growth and myelination regulationlaminins, 337, 339netrins, 340–341proteoglycans, 339

slits, 341–342tenascins, 339–340thrombospondins, 340

central synapse functionchondroitin sulfate proteoglycans, 344

neuronal pentaxins, 345reelin, 344–345thrombospondins, 345

neural stem cell behavior and neuronal migrationextracellular matrix function

laminins, 334–335proteoglycans, 335–336reelin, 336–337tenascins, 336

overview, 333–334

peripheral nerve axonal envelopment andmyelination, 32–33

thrombospondin function, 111

Index

394


Nidogen, laminin complex and linkage to type IVcollagen, 25–26

Nitric oxide (NO), thrombospondin and signalingantagonism, 110–111

NMJ. See Neuromuscular junctionNO. See Nitric oxideNoggin, 362Notch, 109

OOligodendrocyte precursor cell (OPC), 340OPC. See Oligodendrocyte precursor cell

Osteoblast, thrombospondin function, 111

PPAK, 268Papilin, basement membrane function, 29PCP. See Planar cell polarityPDGF. See Platelet-derived growth factorPericyte, recruitment and vascular basement membrane

assembly within vascular guidancetunnels, 326–327

Perlecan. See also Heparan sulfate proteoglycanslinkage to cell surface, 26mutant phenotypes, 69

Planar cell polarity (PCP), 159–160Plasmin, extracellular matrix degradation, 277Platelet

aggregation, 380–381

extracellular matrix interactions in adhesion,373–374

relative contributions of receptors and extracellularmatrix components to thrombosis andhemostasis, 381–382

Platelet-derived growth factor (PDGF)extracellular matrix binding, 27, 82fibril association, 157fibrosis role, 364

Podosome, 264–265

Proteoglycans. See also specific proteoglycansclassification, 4–5growth factor tethering, 27

PSACH. See PseudoachondroplasiaPseudoachondroplasia (PSACH), thrombospondin

defects, 115PTB domain, 174Pyrogenic sterile arthritis, pyoderma, gangrenosum,

and acne (PAPA), 265

RRab5, 80

Rac, 246, 268, 317Radial glial cell (RGC), 333–334, 336RE1 Silencing Factor (REST), 334–335

Reelincentral synapse function, 344–345neural stem cell behavior and neuronal migration

role, 336–337

phylogeny, 13–14REST. See RE1 Silencing FactorRGC. See Radial glial cellRGD motif, 107, 131, 153, 175–176, 192–193,

228–229, 249, 336

RHAMM, 207Rho

adhesion regulation, 209, 265–267fibrillogenesis role, 155force signaling, 250

vascular cord formation role, 317RIAM, 263Rigidity, extracellular matrix

overview, 203

remodeling effects, 283spread area, 251–252

ROCK, 70

SSarcolemma, stabilization, 32SCO-spondin, 340Serglycin, mutant phenotypes, 69Skin

aging effects, 363cancer

extracellular matrix, 364–366wound healing similarity, 366

epidermal stem cellintegrin–extracellular matrix interaction

regulation of stem cell fate, 361–362markers, 359–361

epidermal–dermal junction, 31–32

extracellular matrixheterogeneity, 359prospects for study, 366

fibrosis, 364, 366hemidesmisomes and epidermal integrity role,

226–227hyperproliferation and wound healing,

363–364non-cell autonomous functions of epidermal

integrins and extracellular matrix, 362

structure, 357–358Slits, axonal growth and myelination regulation, 341–342Smooth muscle cell

thrombospondin in migration and proliferation, 110

vasculature, 372Squamous cell carcinoma. See SkinSrc

adhesion turnover role, 268vascular cord formation role, 317

Index

395


SRF, 361SSS. See Stiff skin syndromeStem cell

differentiation and extracellular matrix dynamics,

290–291epidermal stem cell

integrin–extracellular matrix interactionregulation of stem cell fate, 361–362

markers, 359–361

heparan sulfate proteoglycans in niche, 84–85neural stem cell. See Neuron

Stiff skin syndrome (SSS), 187, 191Syndecans. See also Heparan sulfate proteoglycans

coreceptor activity, 79–81

development role, 82fibrillogenesis role, 155integrin interactions, 76, 81mutant phenotypes, 67–68

TTalin, integrin signaling, 231, 233Tat, 80Tenascins

axonal growth and myelination regulation,339–340

cancer invasion and metastasis role, 136–138cell adhesion modulation, 132–134evolution, 13–14, 130–132expression regulation, 134–136knockout mouse phenotypes, 138–141

neural stem cell behavior and neuronal migrationrole, 336

tenascin-C discovery, 129–130types, 130

TGF-b. See Transforming growth factor-bThrombosis. See Hemostasis/thrombosisThrombospondins (TSPs)

axonal growth and myelination regulation, 340binding partners, 106–109

central synapse function, 345degradation, 105–106domains

architecture, 99–101structure, 101–102

evolution, 102–103functions

cell studieschondrocyte, 111endothelial cell, 110

myoblast, 111neuron, 111nitric oxide signaling antagonism, 110–111osteoblast, 111

smooth muscle cell migration andproliferation, 110

Drosophila studies, 112human disease, 115–116mouse studies

cancer models, 114–115

knockout mice, 112–114prospects for study, 116single nucleotide polymorphisms, 115synthesis, 103, 105tissue expression patterns, 103–105

TSP-5/COMP oligomerization domain,115–116

Tie-2, 320Tissue plasminogen activator (tPA), 282, 382tPA. See Tissue plasminogen activator

Transforming growth factor-b (TGF-b)activation

activator types, 193integrin avb5, 194–195

modes, 195overview, 184–187redundancy among growth factor isoforms

and integrin activators, 193–194RGD-binding integrins, 192–193

diseases, 190–192extracellular matrix binding, 8, 27fibrosis role, 364force effects on processing, 251integrin cross talk, 184–185, 192–195

isoforms, 184knockout mouse phenotypes, 184–185, 194latent transforming growth factor-b binding protein

fibrillinshomology, 187

interactions, 189–190functional overview, 185–186mutations, 191–192structure, 187–188

prospects for study, 195thrombospondin interactions, 108–109

TSPs. See Thrombospondins

UuPA. See Urokinase plasminogen activatorUrokinase plasminogen activator (uPA), 282Usherin, basement membrane function, 28

VVascular cord. See AngiogenesisVascular endothelial growth factor (VEGF). See also

Angiogenesis; Vasculogenesisangiogenesis role, 319–320

extracellular matrix binding, 27heparan sulfate proteoglycan coreceptor, 79thrombospondin interactions, 108–109

Index

396


Vasculogenesis, adult angiogenesis comparisonintegrins, 321, 324knockout mouse phenotypes, 322–323overview, 320–321

VASP, 251VEGF. See Vascular endothelial growth factorVersican, 339VLDLR, 336von Willebrand factor (VWF)

hemostasis role, 375–377processing, 374–375structure, 374

VWF. See von Willebrand factor

WWASP, 265Wnt, fibrillogenesis regulation in development,

159–160Wound healing

cancer similarity, 366epidermal hyperproliferation, 363–364fibrin clot cellular interactions, 382

ZZyxin, force signaling, 250–251

Index

397


i-viii cshperspect-ecm-fm 1. · some of these processesand the involvement of the ecm. matrix...

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