Extracellular Matrix: Pathobiology and Signaling (eBook)

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Nikos K. Karamanos, Biochem. Lab, Department of Chemistry, University of Patras, Greece.

Section-Editors: Donald Gullberg, Department of Biomedicine, University of Bergen, Norway; Paraskevi Heldin,Ludwig Institute for Cancer Research, Uppsala University,Sweden; Liliana Schaefer, Institute of General Pharmacology and Toxicology, Goethe-University, Frankfurt,Germany; Ruggero Tenni, Department of Biochemistry, Pavia University, Italy; Achilleas Theocharis, Department of Chemistry, University of Patras, Greece; Jan-Olof Winberg, Department of Medical Biology, University of Tromsø, Norway.

Preface 19
Comments on the book Extracellular Matrix: Pathobiology & Signaling by Dick Heinegård
About the Editor/Section Editors 25
List of contributing authors 29
Abbreviations and acronyms used 39
1 An introduction to the extracellular matrix molecules and their importance in pathobiology and signaling 51
1.1 Extracellular matrix: a functional scaffold 53
1.1.1 ECM components: structural and functional properties 54
1.1.2 Matrix remodeling is accomplished by proteolytic enzymes 62
1.1.3 Cell surface receptors mediate cell-cell and cell-matrix interactions 64
1.1.4 Take-home message 67
2 Insights into the function of glycans 71
2.1 Introduction 73
2.2 Metabolic control of hyaluronan synthesis 76
2.2.1 Introduction 76
2.2.2 Transcription of hyaluronan synthases 77
2.2.3 UDP-sugar substrates as limiting factors in hyaluronan synthesis 79
2.2.4 Posttranslational processing of HAS 82
2.2.5 Challenges and future prospects 85
2.2.6 Take-home message 85
2.3 Multiple roles of hyaluronan as a target and modifier of the inflammatory response 89
2.3.1 Introduction 89
2.3.2 Endothelial permeability 90
2.3.3 Angiogenesis 90
2.3.4 Mechanisms of hyaluronan degradation 91
2.3.5 Consequences of hyaluronan fragmentation 91
2.3.6 Hyaluronan cross-talk with leukocytes 92
2.3.7 Adhesion of leukocytes to hyaluronan 96
2.3.8 Hyaluronan removal in the late phase of inflammation 98
2.3.9 Local clearance of hyaluronan 98
2.3.10 Chronic inflammation 99
2.3.11 Hyaluronan increase in wounds 100
2.3.12 Support of migration and proliferation 101
2.3.13 TGF-ß and myofibroblasts 102
2.3.14 Therapeutic applications 103
2.3.15 Future perspectives 103
2.3.16 Take-home message 104
2.4 Roles of sulfated and nonsulfated glycosaminoglycans in cancer growth and progression-therapeutic implications 116
2.4.1 Introduction 116
2.4.2 Heparin and heparan sulfate affect key tumor cell functions 117
2.4.3 Chondroitin sulfate participates in cancer cell, tumor stroma, and tumor microenvironement interactions to affect cancer progression 120
2.4.4 HA synthesis is correlated to cancer progression 122
2.4.5 Challenges and future prospects 124
2.4.6 Take-home message 126
2.5 Heparan sulfate design: regulation of biosynthesis 134
2.5.1 Heparan sulfate – an extracellular component with variable structure 134
2.5.2 How is heparan sulfate synthesized and which enzymes contribute? 135
2.5.3 Fine-tuning of heparan sulfate structure in the right place, at the right time 138
2.5.4 Disturbed heparan sulfate biosynthesis in human pathobiology 142
2.5.5 Take-home message 143
2.6 Bone and skin disorders caused by a disturbance in the biosynthesis of chondroitin sulfate and dermatan sulfate 148
2.6.1 Introduction 148
2.6.2 Biosynthetic pathways of CS and DS chains 150
2.6.3 Human congenital disorders caused by mutations of the enzymes involved in the biosynthesis of CS and DS 155
2.6.4 Challenges and future prospects 158
2.6.5 Take-home message 162
2.6.6 Abbreviations 162
2.7 Biological functions of branched N-glycans related to physiology and pathology of extracellular matrix 169
2.7.1 Introduction 169
2.7.2 Synthesis of branched N-glycans 169
2.7.3 Effect of N-glycosylation on ECM formation 172
2.7.4 Complexity of N-glycan branch modulates cellular functions via clustering cell surface proteins 173
2.7.5 Branched N-glycans regulate the biological functions of integrins 174
2.7.6 The mutual regulation of N-glycosylation and cadherins 175
2.7.7 Challenges and future prospects 176
2.7.8 Take-home message 177
3 Proteoglycans: structure, pathobiology, and signaling 183
3.1 Introduction 185
3.2 Aggrecan in skeletal development and regenerative medicine 191
3.2.1 Introduction 191
3.2.2 Aggrecan in skeletal development 191
3.2.3 Aggrecan in regenerative medicine 194
3.2.4 Take-home message 198
3.3 The pathobiology of versican 204
3.3.1 Introduction 204
3.3.2 Cardiovascular disease 204
3.3.3 Cancer 209
3.3.4 Lung 211
3.3.5 Eye 211
3.3.6 Concluding remarks 212
3.3.7 Take-home message 213
3.4 The biology of perlecan and its bioactive modules 221
3.4.1 Introduction 221
3.4.2 Discovery 221
3.4.3 Expression and localization 221
3.4.4 Protein family 222
3.4.5 The HSPG2 gene 222
3.4.6 Domain structure and known interactions 223
3.4.7 Genetic links to diseases 226
3.4.8 Genetic models 226
3.4.9 Perlecan role in cancer 227
3.4.10 Perlecan role in vascular biology and angiogenesis 228
3.4.11 Conclusions and future directions 230
3.4.12 Take-home message 231
3.5 Small leucine-rich proteoglycans: multifunctional signaling effectors 235
3.5.1 Introduction 235
3.5.2 Physiological functions 235
3.5.3 Pathobiology of class I SLRPs 236
3.5.4 Pathobiology of class II SLRPs 239
3.5.5 Pathobiology of class III SLRPs 240
3.5.6 Take-home message 241
3.6 Structure and function of syndecans 247
3.6.1 Syndecan stucture 247
3.6.2 Function of syndecans 249
3.6.3 Syndecan domains and their roles 251
3.6.4 Take-home message 254
3.7 The glypican family 259
3.7.1 The structure of glypicans 259
3.7.2 The functions of glypicans 260
3.7.3 Pathobiology of glypicans 264
3.7.4 Future research 266
3.7.5 Take-home message 266
3.8 Serglycin proteoglycan: implications for thrombosis, inflammation, atherosclerosis, and metastasis 271
3.8.1 Introduction 271
3.8.2 Cloning and cell and tissue localization of serglycin 271
3.8.3 Cell-specific serglycin structure 272
3.8.4 Regulation of serglycin expression 272
3.8.5 Binding of cell-specific serglycin to biologically active proteins 272
3.8.6 Serglycin in hematopoietic cells 273
3.8.7 Serglycin in nonhematopoietic cells 274
3.8.8 The serglycin knockout mouse 275
3.8.9 Challenges and future prospects 277
3.8.10 Take-home message 278
4 Matrix proteinases: biological significance in health and disease 283
4.1 Introduction 285
4.2 Extracellular functions of cysteine proteases 289
4.2.1 Introduction 289
4.2.2 Cysteine proteases and their inhibitors 290
4.2.3 Endogenous inhibitors of cysteine proteases 291
4.2.4 Cysteine proteases and their inhibitors in diseases 294
4.2.5 Pharmacological targeting of cysteine proteases 301
4.2.6 Take-home message 303
4.3 Plasmin and the plasminogen activator system in health and disease 311
4.3.1 Introduction 311
4.3.2 Plasmin 311
4.3.3 Plasminogen activators 316
4.3.4 Inhibitors of plasminogen activators 320
4.3.5 Plasmin substrates 321
4.3.6 Inhibitors of plasmin 324
4.3.7 Plasmin system in cancer 325
4.3.8 Take-home message 327
4.4 Matrix metalloproteinase complexes and their biological significance 341
4.4.1 Introduction 341
4.4.2 MMP structure and classification 343
4.4.3 MMP complexes 344
4.4.4 Take-home message 358
4.5 The ADAMTS family of metalloproteinases 365
4.5.1 Introduction 365
4.5.2 The ADAMTS family 367
4.5.3 Three-dimensional structures of ADAMTSs 370
4.5.4 Procollagen N-proteinases (ADAMTS2, 3, and 14) 372
4.5.5 Aggrecanases 373
4.5.6 Inhibition of angiogenesis by ADAMTSs 377
4.5.7 Von Willebrand factor-cleaving proteinase: ADAMTS13 378
4.5.8 ADAMTS18 and dissolution of platelet aggregates 379
4.5.9 Atherosclerosis 380
4.5.10 ADAMTSs and morphogenesis 380
4.5.11 Wound healing 382
4.5.12 Ovulation 383
4.5.13 Future prospects 384
4.5.14 Take-home message 384
4.6 Proteinases in wound healing 393
4.6.1 Introduction 393
4.6.2 Overview of cutaneous wound repair 393
4.6.3 Hemostasis and inflammation 394
4.6.4 Reepithelialization 395
4.6.5 Granulation tissue formation 395
4.6.6 Tissue remodeling and wound maturation 396
4.6.7 Growth factors and cytokines regulating cutaneous wound healing 396
4.6.8 Proteolysis in cutaneous wound healing 398
4.6.9 PA-plasmin system 398
4.6.10 Matrix metalloproteinases 401
4.6.11 ADAM proteinases 406
4.6.12 ADAMTS proteinases 407
4.6.13 TIMPs and chemical targeting of metalloproteinases 408
4.6.14 Proteolysis in aberrant cutaneous wound healing 409
4.6.15 Targeting proteolysis – applications for wound-healing therapy 413
4.6.16 Take-home message 414
4.7 Rock, paper, and molecular scissors: regulating the game of extracellular matrix homeostasis, remodeling, and inflammation 427
4.7.1 Proteases 427
4.7.2 Matrix metalloproteinases 428
4.7.3 Natural inhibitors of MMPs 430
4.7.4 MMPs in cancer 431
4.7.5 MMPs in Inflammation 433
4.7.6 MMP inhibitors and clinical trials 434
4.7.7 The protease web 435
4.7.8 Degradomics 435
4.7.9 The CLIP-CHIP, a dedicated and focused microarray for every protease and inhibitor 436
4.7.10 Classic biochemical approaches 436
4.7.11 Sodium dodecyl sulfate polyacrylamide gel electrophoresis, zymography, mass spectrometry, and high-performance liquid chromatography 437
4.7.12 Proteomic identification of protease cleavage site specificity 438
4.7.13 Yeast two-hybrid analyses: exosite scanning and inactive-catalytic-domain capture 438
4.7.14 Amino-terminal-oriented mass spectrometry of substrates 439
4.7.15 Quantitative N- and C-terminal proteomics for substrate discovery 439
4.7.16 N-terminal combined fractional diagonal chromatography 440
4.7.17 N-terminal amine isotopic labeling of substrates 441
4.7.18 C terminomics and C-terminal amine-based isotope labeling of substrates 442
4.7.19 Perspectives and Take-home message 443
5 ECM cell surface receptors 451
5.1 Introduction 453
5.2 Integrin function in heart fibrosis: mechanical strain, transforming growth factor-beta 1 activation, and collagen glycation 456
5.2.1 Introduction 456
5.2.2 Cardiac fibrosis – the players 457
5.2.3 ECM posttranslational modifications in fibrosis: type 1 and type 2 diabetes 461
5.2.4 Interaction of integrins with glycated collagen 465
5.2.5 TGF-ß and integrins - a close relationship 467
5.2.6 Conclusions 471
5.2.7 Take-home message 471
5.3 Cancer-associated fibroblast integrins as therapeutic targets in the tumor microenvironment 482
5.3.1 Introduction 482
5.3.2 CAF Biology 482
5.3.3 Integrins on CAFs 483
5.3.4 Integrin function on CAF precursors 488
5.3.5 Integrin function in CAF differentiation 489
5.3.6 CAF integrins and tumor cell proliferation 491
5.3.7 Integrin function in CAF-promoted invasion and metastasis 491
5.3.8 Summary 494
5.4 Discoidin domain receptors: non-integrin collagen receptors on the move 501
5.4.1 Introduction 501
5.4.2 Collagen and collagen receptors 501
5.4.3 Discoidin domain receptor subfamily of receptor tyrosine kinases 504
5.4.4 Functions of DDRs 508
5.4.5 Conclusions 512
5.4.6 Take-home message 512
5.5 Syndecans as receptors for pericellular molecules 517
5.5.1 Introduction 517
5.5.2 Syndecans as cell surface ECM receptors 519
5.5.3 Syndecans as receptors mediating endocytosis 523
5.5.4 Syndecans as receptors for growth factors and chemokines 523
5.5.5 Perspective – specificity of syndecans and their signaling responses 527
5.5.6 Take-home message 528
5.6 CD44: a Sensor of tissue damage critical for restoring homeostasis 534
5.6.1 Introduction 534
5.6.2 CD44 structure and processing 535
5.6.3 Hyaluronan and other ligands of CD44 535
5.6.4 CD44-mediated signaling 536
5.6.5 CD44 function in mesenchymal stromal cells 537
5.6.6 CD44 function in leukocytes 541
5.6.7 Role of CD44 in the resolution of inflammation 542
5.6.8 CD44 in disease and as a potential therapeutic target 542
5.6.9 Concluding remarks 543
5.6.10 Take-home message 544
6 Collagen: insights into the folding, assembly and functions 549
6.1 Introduction 551
6.2 Trimerization domains in collagens: chain selection, folding initiation, and triple-helix stabilization 556
6.2.1 Introduction 556
6.2.2 Chain selection and trimerization 557
6.2.3 Trimerization domains and triple-helix folding and stabilization 563
6.2.4 Pathologies associated with trimerization domains 564
6.2.5 Future prospects and challenges 565
6.2.6 Take-home message 566
6.3 Structural basis of collagen missense mutations 571
6.3.1 Introduction: collagens and disease 571
6.3.2 Peptide models of collagen mutations 571
6.3.3 Computational analysis 578
6.3.4 Collagen mutations in a recombinant bacterial system 580
6.3.5 Summary and take-home message 585
6.4 Roles and regulation of BMP1/Tolloid-like proteinases: collagen/matrix assembly, growth factor activation, and beyond 589
6.4.1 Introduction 589
6.4.2 BMP1/Tolloid-like proteinases 589
6.4.3 Substrates 592
6.4.4 Endogenous regulators of activity 600
6.4.5 Meprins and matrix assembly 604
6.4.6 Conclusions and take-home message 605
6.5 Supramolecular assembly of type I collagen 612
6.5.1 Introduction 612
6.5.2 The multimodal fibrils: tendon, bone, and ligaments 613
6.5.3 The unimodal fibrils: cornea, sheaths, and blood vessels 617
6.5.4 Take-home message 621
6.6 Collagen interactomes: mapping functional domains and mutations on fibrillar and network-forming collagens 625
6.6.1 Collagen interactomes 625
6.6.2 Type I collagen interactome 626
6.6.3 Type IV collagen interactome 632
6.6.4 Type III collagen interactome 636
6.6.5 Type II collagen 637
6.6.6 Type X collagen 637
6.6.7 Future perspectives 638
6.6.8 Take-home message 638
6.7 Collagen-binding proteins 642
6.7.1 Introduction 642
6.7.2 Heat-shock protein 47 643
6.7.3 Pigment epithelium-derived factor 644
6.7.4 Fibronectin 645
6.7.5 Von Willebrand factor 646
6.7.6 Glycoprotein VI 646
6.7.7 Leukocyte-associated immunoglobulin-like receptor-1 647
6.7.8 Discoidin domain receptors (DDR) 647
6.7.9 Secreted protein acidic and rich in cysteine 648
6.7.10 Take-home message 650
7 Emerging aspects in extracellular matrix pathobiology 653
7.1 Introduction 655
7.2 Extracellular matrix in breast cancer: permissive and restrictive influences emanating from the stroma 660
7.2.1 Introduction 660
7.2.2 The extracellular context in the mammary gland 660
7.2.3 The physical role of connective tissue stroma 663
7.2.4 The proteomic lesson 666
7.2.5 Concluding remarks 669
7.2.6 Challenges and future prospects 671
7.2.7 Take-home message 671
7.3 EMMPRIN/CD147: potential functions in tumor microenvironment and therapeutic target for human cancer 676
7.3.1 Introduction 676
7.3.2 Protease-inducing activity of EMMPRIN: role in tumor cell invasion 679
7.3.3 Role of EMMPRIN in myofibroblast differentiation 680
7.3.4 Role of EMMPRIN in angiogenesis 681
7.3.5 Shedding of EMMPRIN 682
7.3.6 EMMPRIN as a therapeutic target for human cancer 683
7.3.7 Take-home message 684
7.4 Implication of hyaluronidases in cancer growth, metastasis, diagnosis, and treatment 689
7.4.1 Introduction 689
7.4.2 Hyaluronidases in cancer 690
7.4.3 Regulation of hyaluronidase activity 693
7.4.4 Hyaluronidases and cell cycle progression 694
7.4.5 Anticancer properties of hyaluronidases 696
7.4.6 Further medical applications of hyaluronidases 698
7.4.7 Challenges and future prospects 699
7.4.8 Take-home message 699
7.5 Structure-function relationship of syndecan-1, with focus on nuclear translocation and tumor cell behavior 703
7.5.1 Syndecans 703
7.5.2 Structural organization 703
7.5.3 Functional domains and cellular interactions 704
7.5.4 Cellular distribution and nuclear translocation 706
7.5.5 Nuclear interactions 708
7.5.6 Syndecan-1 expression in normal tissues 710
7.5.7 Syndecan-1 in cancers 711
7.5.8 Syndecan expression affects tumor cell behavior 714
7.5.9 Potential for translation 716
7.5.10 Take-home message 718
7.6 Serglycin: a novel player in the terrain of neoplasia 727
7.6.1 Introduction 727
7.6.2 Expression of serglycin in malignancies 728
7.6.3 Regulation of serglycin gene expression 729
7.6.4 Functional importance of serglycin in malignancies 729
7.6.5 Serglycin regulates the secretion of proteolytic enzymes 732
7.6.6 Serglycin regulates the secretion and properties of inflammatory mediators 733
7.6.7 Take-home message 735
7.7 Quantifying cell-ECM pathobiology in 3D 739
7.7.1 Introduction 739
7.7.2 Importance of three-dimensional culture systems 739
7.7.3 Advancements in 3D quantification 742
7.7.4 Future directions 747
7.7.5 Take-home message 748
7.8 Diabetic foot infections 753
7.8.1 Introduction 753
7.8.2 Serological diagnosis of osteitis in foot infection in diabetes mellitus 758
7.8.3 Conclusion and summary 760
7.8.4 Take-home message 760
8 Targeting tumor microenvironment at the ECM level 767
8.1 Introduction 769
8.2 Targeting the tumor microenvironment in cancer progression 773
8.2.1 Targeting the tumor microenvironment 773
8.2.2 Cancer stem cells 778
8.2.3 Tumor angiogenesis: new concepts about the tumor microenvironment 781
8.2.4 CD44 in tumor biology 782
8.2.5 Take-home message 786
8.3 Growth factor signaling and extracellular matrix 791
8.3.1 Introduction 791
8.3.2 Interplay of growth factors and ECM 791
8.3.3 Growth factor signaling regulates ECM composition 794
8.3.4 Effect of ECM on growth factor action 799
8.3.5 Pharmacological Interventions 801
8.3.6 Take-home message 803
8.4 Targeting protein-glycan interactions at cell surface during EMT and hematogenous metastasis: consequences on tumor invasion and metastasis 813
8.4.1 Introduction 813
8.4.2 Tumor invasion and metastasis 815
8.4.3 Unique glycosaminoglycans from marine invertebrates and their potential antitumor activity 822
8.4.4 Challenges and future prospects 825
8.4.5 Take-home message 826
8.5 Pharmacological targeting of proteoglycans and metalloproteinases: an emerging aspect in cancer treatment 835
8.5.1 Introduction 835
8.5.2 The importance of targeting at ECM level in tumor progression 835
8.5.3 Pharmacological targeting of proteoglycans 836
8.5.4 Pharmacological targeting of matrix metalloproteinases 842
8.5.5 Pharmacological targeting of PGs/MMPs at the proteasome level 845
8.5.6 Concluding remarks 846
8.5.7 Take-home message 847
8.6 Targeting syndecan shedding in cancer 852
8.6.1 Introduction 852
8.6.2 Syndecan sheddases 853
8.6.3 Tissue inhibitors of metalloproteinases 854
8.6.4 Syndecan shedding and cancer 854
8.6.5 Future prospects 858
8.6.6 Take-home message 859
8.7 PG receptors with phosphatase action in cancer and angiogenesis 863
8.7.1 Introduction 863
8.7.2 Glycosylated transmembrane protein phosphatase receptors 865
8.7.3 RPTP-ß/. 867
8.7.4 Conclusions 870
8.7.5 Take-home message 870
8.8 Heparanase, a multifaceted protein involved in cancer, chronic inflammation, and kidney dysfunction 874
8.8.1 Introduction 874
8.8.2 Involvement of heparanase in cancer progression 878
8.8.3 Heparanase and inflammation 886
8.8.4 Heparanase and diabetic nephropathy 890
8.8.5 Challenges and future perspectives 892
8.8.6 Take-home message 893
8.9 Delivery systems targeting cancer at the level of ECM 905
8.9.1 Introduction 905
8.9.2 Targeting cancer 907
8.9.3 CD44-HA in tumor biology 910
8.9.4 Strategies that target CD44 to perturb HA-CD44 interaction in tumors 913
8.9.5 Take-home message 918
Index 923