Presenting a comprehensive overview of the multifaceted field of extracellular matrix degradation by extracellular proteases, this reference focuses on therecently elucidated functions of proteolytic systems, such as plasminogen activators, ADAMS and other matrix proteases in physiological and pathological tissue remodeling. It specifically addresses the role of extracellular proteasesin cancer cell invasion, stroke and Alzheimer's disease, describing the basicbiochemistry behind these disease states, as well as therapeutic strategies based on protease inhibition. With its trans-disciplinary scope, this referencebridges the gap between fundamental research and biomedical and pharmaceutical application, making this required reading for basic and applied scientists in the molecular life sciences. INDICE: List of Contributors XVIntroduction 1Niels Behrendt1 Matrix Proteases and the Degradome 5Clara Soria-Valles, Carlos L´opez-Ot´ýn, and Ana Guti´errez-Fern´andez1.1 Introduction 51.2 Bioinformatic Tools for the Analysis of Complex Degradomes 61.3 Evolution of Mammalian Degradomes 81.3.1 Human Degradome 81.3.2 Rodent Degradomes 101.3.3 Chimpanzee Degradome 101.3.4 Duck-Billed Platypus Degradome 111.3.5 Other Degradomes 121.4 Human Diseases of Proteolysis 131.5 Matrix Proteases and Their Inhibitors 14Acknowledgments 17References 172 The Plasminogen Activation System in Normal Tissue Remodeling 25Vincent Ellis2.1 Introduction 252.2 Biochemical and Enzymological Fundamentals 262.2.1 Plasminogen 272.2.2 Regulation of the Plasminogen Activation System 282.3 Biological Roles of the Plasminogen Activation System 302.3.1 Congenital Plasminogen Deficiencies 312.3.2 Intravascular Fibrinolysis 322.3.3Extravascular Fibrinolysis Ligneous Conjunctivitis 322.3.4 Congenital Inhibitor Deficiencies 332.4 Tissue Remodeling Processes 342.4.1 Wound Healing 342.4.2 Vascular Remodeling 352.4.3 Fibrosis 362.4.4 Nerve Injury 382.4.5 Rheumatoid Arthritis 382.4.6 Complex Tissue Remodeling 402.4.7 Angiogenesis 402.4.8 uPAR Cinderella Finds Her Shoe 422.5 Conclusions 44References 453 Physiological Functions of Membrane-Type Metalloproteases 57Kenn Holmbeck3.1 Introduction 573.2 Historical Perspective 573.3 Activation of the Activator 593.4 Potential Roles of MT-MMPs and Discovery of a Human MMP Mutation 593.5 MT-MMP Function? 603.6 Physiological Roles of MT1-MMP in the Mouse 613.7 MT1-MMP Function in Lung Development 633.8 MT1-MMP Is Required for Root Formation and Molar Eruption 643.9 Identification of Cooperative Pathways for Collagen Metabolism 643.10 MT-MMP Activity in the Hematopoietic Environment 653.11 Physiological Role of MT2-MMP 663.12 MT-Type MMPs Work in Concert to Execute Matrix Remodeling 673.13 MT4-MMP an MT-MMP with Elusive Function 693.14 MT5-MMP Modulates Neuronal Growth and Nociception 693.15 Summary and Concluding Remarks 70Acknowledgment 71References 714 Bone Remodeling: Cathepsin K in Collagen Turnover 79Dieter Br¨omme4.1 Introduction 794.2 Proteolytic Machinery of Bone Resorption and Cathepsin K 804.3 Specificity and Mechanism of Collagenase Activity of Cathepsin K824.4 Role of Glycosaminoglycans in Bone Diseases 864.5 Development of Specific Cathepsin K Inhibitors and Clinical Trials 874.6 Off-Target and Off-Site Inhibition 894.7 Conclusion 91Acknowledgments 91References 915 Type-II Transmembrane Serine Proteases: Physiological Functions and Pathological Aspects 99Gregory S. Miller, Gina L. Zoratti, and Karin List5.1 Introduction 995.2 Functional/Structural Properties of TTSPs 995.3 Physiology and Pathobiology 1045.3.1 Hepsin/TMPRSS Subfamily 1045.3.2 Corin Subfamily 1055.3.3 Matriptase Subfamily 1065.3.4 HAT/DESC1 Subfamily 1105.3.5 TTSPs in Cancer 111References 1146 Plasminogen Activators in Ischemic Stroke 127Gerald Schielke and Daniel A. Lawrence6.1 Introduction 1276.2 Rationale for Thrombolysis after Stroke 1286.2.1 Clinical Trials: Overview 1296.3 Preclinical Studies 1316.3.1 Localization of PAs, Neuroserpin, and Plasminogen in the Brain 1316.4 The Association of Endogenous tPA with Excitotoxic and Ischemic Brain Injury 1346.4.1 Excitotoxicity 1346.4.2 Focal Ischemia 1356.4.3 Global Ischemia 1376.5 Mechanistic Studies of tPA inExcitotoxic and Ischemic Brain Injury 1376.5.1 tPA and the NMDA Receptor 1376.5.2 tPA and the BloodBrain Barrier 1386.5.3 tPA and the BloodBrain Barrier MMPs 1396.5.4 tPA and the BloodBrain Barrier LRP 1406.6 tPA and the BloodBrainBarrierPDGF-CC 1416.7 Summary 143Acknowledgments 144References 1457 BacterialAbuse of Mammalian Extracellular Proteases during Tissue Invasion and Infection 157Claudia Weber, Heiko Herwald, and Sven Hammerschmidt7.1 Introduction 1577.2 Tissue and Cell Surface Remodeling Proteases 1587.2.1 Matrix Metalloproteinases (MMPs) 1587.2.2 A Disintegrin and Metalloproteinases (ADAMs) 1607.2.3 A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) 1617.3 Proteases of the Blood Coagulation and the Fibrinolytic System 1627.3.1 Proteases of the Blood Coagulation System 1627.3.2 Proteases of the Fibrinolytic System 1647.4 Contact System 1687.4.1 Mechanisms of Bacteria-Induced Contact Activation 1697.5 Conclusion and Future Prospectives 170Acknowledgments 172References 1728 Experimental Approaches for Understanding the Role of Matrix Metalloproteinases in Cancer Invasion 181Elena Deryugina8.1 Introduction: Functional Roles of MMPs in Physiological Processes Involving the Induction and Sustaining of Cancer Invasion 1818.2 EMT: a Prerequisite of MMP-Mediated Cancer Invasion or a Coordinated Response to Growth-Factor-Induced MMPs? 1828.2.1 MMP-Induced EMT 1838.2.2 EMT-Induced MMPs 1858.3 Escape from the Primary Tumor: MMP-Mediated Invasion of Basement Membranes 1868.3.1 In vitro Models of BM Invasion: Matrigel Invasion in Transwells 1868.3.2 Ex Vivo Models of BM Invasion: Transmigration through the Intact BM 1888.3.3 In Vivo Models of BM Invasion: Invasion ofthe CAM in Live Chick Embryos 1898.4 Invasive Front Formation: Evidence for MMP Involvement In Vivo 1898.4.1 MMP-Dependent Invasion in Spontaneous Tumors Developing in Transgenic Mice 1908.4.2 MMP-Dependent Invasion of Tumor Grafts in MMP-Competent Mice 1918.4.3 Invasion of MMP-Competent Tumor Grafts in MMP-Deficient Mice 1928.5 Invasion at the Leading Edge: MMP-Mediated Proteolysis of Collagenous Stroma 1938.5.1 Collagen Invasion in Transwells 1938.5.2 Invasion of Collagen Matrices by Overlaid Tumor Cells 1948.5.3 Models of 3D Collagen Invasion 1958.5.4 Invasion of Collagenous Stroma In Vivo 1968.5.5 Dynamic Imaging of ECM Proteolysis during Path-Making In vitro and In Vivo 1978.6 Tumor Angiogenesis and Cancer Invasion: MMP-Mediated Interrelationships 1978.6.1 Angiogenic Switch: MMP-9-Induced Neovascularization as a Prerequisite for Blood-Vessel-Dependent Cancer Invasion 1988.6.2 Mutual Reliance of MMP-Mediated Angiogenesis and Cancer Invasion 2008.6.3 Apparent Distinction between MMP-Mediated Tumor Angiogenesis and Cancer Invasion 2018.7 Cancer Cell Intravasation: MMP-Dependent Vascular Invasion 2028.8 Cancer Cell Extravasation: MMP-Dependent Invasion of the Endothelial Barrier and Subendothelial Stroma 2048.8.1 Transmigration across Endothelial Monolayers In Vitro 2048.8.2 Tumor Cell Extravasation In Vivo 2058.9 Metastatic Site: Involvement of MMPs in the Preparation, Colonization, and Invasion of Distal Organ Stroma 2068.9.1 MMPs as Determinants of Organ-Specific Metastases 2078.9.2 MMP-Dependent Preparation of the PreMetastatic Microenvironment 2088.9.3 Invasive Expansion of Cancer Cells at the MetastaticSite 2108.10 Perspectives: MMPs in the Early Metastatic Dissemination and Awakening of Dormant Metastases 211References 2129 Plasminogen Activators and Their Inhibitors in Cancer 227Joerg Hendrik Leupold and Heike Allgayer9.1 Introduction 2279.2 The Plasminogen Activator System 2289.2.1 Molecular Characteristics and Physiological Functions of the u-PA System 2289.2.2 Expression in Cancer 2309.2.3 Regulation of Expression of the u-PA System in Cancer 2319.2.4 Regulation of Cell Signaling by the u-PA System 2359.2.5 Conclusion 238References 23810 Protease Nexin-1 a Serpin with a Possible Proinvasive Role in Cancer 251Tina M. Kousted, Jan K. Jensen, Shan Gao, and Peter A. Andreasen10.1 Introduction Serpins and Cancer 25110.2 History of PN-1 25210.3 General Biochemistry of PN-1 25310.4 Inhibitory Properties of PN-1 25410.5 Binding of PN-1 and PN-1-Protease Complexes to Endocytosis Receptors of the Low-Density Lipoprotein Receptor Family 25710.6 Pericellular Functions of PN-1 in Cell Cultures 26010.7 PN-1 Expression Patterns 26110.7.1 Expression of PN-1 in Cultured Cells 26110.7.2 Mechanisms of Transcriptional Regulation of PN-1 Expression 26210.7.3 Expression of PN-1 in the Intact Organism 26310.8 Functions of PN-1 in Normal Physiology 26310.8.1 Reproductive Organs 26310.8.2 Neurobiological Functions 26410.8.3 Vascular Functions 26510.9 Functions of PN-1 in Cancer 26610.9.1 PN-1 Expression is Upregulated in Human Cancers, and a High Expression Is a Marker fora Poor Prognosis 26610.9.2 Studies with Cell Cultures and Animal Tumor ModelsIndicate a Proinvasive Role of PN-1 26710.10 Conclusions 270References 27111 Secreted Cysteine Cathepsins Versatile Players in Extracellular Proteolysis 283Fee Werner, Kathrin Sachse, and Thomas Reinheckel11.1 Introduction 28311.2 Structure and Function of Cysteine Cathepsins 28311.3 Synthesis, Processing, andSorting of Cysteine Cathepsins 28411.4 Extracellular Enzymatic Activity of Lysosomal Cathepsins 28611.5 Endogenous Cathepsin Inhibitors as Regulators of Extracellular Cathepsins 28611.6 Extracellular Substrates of Cysteine Cathepsins28711.7 Cysteine Cathepsins in Cancer: Clinical Associations 28711.8 CysteineCathepsins in Cancer: Evidence from Animal Models 28811.9 Molecular Dysregulation of Cathepsins in Cancer Progression 28911.10 Extracellular Cathepsins in Cancer 28911.11 Conclusions and Further Directions 290Acknowledgments 291References 29112 ADAMs in Cancer 299Dorte Stautz, Sarah Louise Dombernowsky, and Marie Kveiborg12.1 ADAMsMultifunctional Proteins 29912.1.1 Structure and Biochemistry 29912.1.2 Biological Functions 30012.1.3 Pathological Functions 30112.2 ADAMs in Tumors and Cancer Progression 30112.2.1 Self-Sufficiency in Growth Signals 30312.2.2 Evasion of Apoptosis 30312.2.3 Sustained Angiogenesis 30412.2.4 Tissue Invasion and Metastasis 30512.2.5 Cancer-Related Inflammation 30612.2.6 TumorStroma Interactions 30712.3 ADAMs in CancerKey Questions Yet to Be Answered 30712.3.1 ADAM Upregulation 30812.3.2 Isoforms 30812.3.3 Proteolytic versus Nonproteolytic Effect 30912.4 The Clinical Potential of ADAMs 30912.4.1 Diagnostic or Prognostic Biomarkers 30912.4.2 ADAMs as Therapeutic Targets 31012.5 Concluding Rem
- ISBN: 978-3-527-32991-5
- Editorial: Wiley-VCH
- Encuadernacion: Cartoné
- Páginas: 416
- Fecha Publicación: 13/06/2012
- Nº Volúmenes: 1
- Idioma: Inglés