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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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Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
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
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Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
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
Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
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
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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
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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
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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
Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
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
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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
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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
Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
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
Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.
Copyright 2012 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press.