inthisresearchfieldandthemanyexcitingdiscoveriessuggeststhattheresearchefforts inthenextdecadewillrevealthemechanismsbywhichthecomponentsoftheplas­ minogensysteminteractandregulatebothplasminactivationandfunctionatacellular level. Plasminogen: Structure, activation, and regulationisdividedintotwosections. Thefirstsectiondealswiththestructureandregulationofplasminogen. Thechapters inthissectionrangefromdiscussionsofthestructureofplasminogenandtheregulation oftheplasminogengenetodiscussionsofthestructureandregulationofplasminogen activatorsandplasminogenactivatorinhibitors. Alsoexaminedistherelativelynewdata concerningthegenerationofanti-angiogenicmoleculesfromplasminogen. Thesecond sectiondealswiththephysiologicalandpathophysiologicalrolesofplasminogenaswell astheconsequencesofplasminogengeneknockout. Discussionsinthissectioninclude examinationoftheroleofplasminogeninhematopoieticmalignancies,tumorcell progression,angiogenesis,mammaryglandinvolution,woundhealing,andbone readsorption. xi xii Preface Inclosing,Iwouldliketothankmyadministrativeassistant,Ms. ViSommerfeld,for herinvaluableassistanceandtimelesseffortswiththeorganizationandeditingofthebook. Lastly,Iwouldliketoacknowledgetheeffortsoftheauthorsoftheindividualchapters, whoareauthorities inthisfield,foragreeingtotaketimefrombusyschedulestoprovide thesechaptersinatimelyfashion. DavidMortonWaisman Contents Part I. Plasminogen: Structure and Regulation 1. Human Plasminogen: Structure, Activation, and Function FrancisJ. Castellino and Victoria A. Ploplis 1. Introduction 3 2. StructureofHumanPlasminogen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2. 1. PrimaryProteinStructure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2. 2. GeneOrganization 5 3. ActivationofHumanPlasminogen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3. 1. ActivationbyPhysiologicalActivators 7 3. 1. 1. Urokinase-type

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I. Plasminogen: Structure and Regulation.- 1. Human Plasminogen: Structure, Activation, and Function.- 1. Introduction.- 2. Structure of Human Plasminogen.- 2.1. Primary Protein Structure.- 2.2. Gene Organization.- 3. Activation of Human Plasminogen.- 3.1. Activation by Physiological Activators.- 3.1.1. Urokinase-type Plasminogen Activator.- 3.1.2. Tissue-type Plasminogen Activator.- 3.2. Activation by Bacterial-derived Plasminogen Activators.- 3.2.1. Streptokinase.- 3.2.2. Staphylokinase.- 4. Targets for Plasmin Activity.- 5. Dysplasminogenemias and Phenotypic Manifestations.- 6. Conclusions.- References.- 2. Plasminogen Activators: Structure and Function.- 1. Introduction.- 2. Serine Proteases.- 3. Urokinase Plasminogen Activator, uPA.- 3.1. Serine Protease Domain.- 3.2. N-terminal Domains.- 3.2.1. KR Module.- 3.2.2. EG Module.- 4. Mechanisms Regulating uPA Function.- 4.1. Zymogen Activation.- 4.2. Zymogen Activity.- 4.3. Reciprocal Zymogen Activation.- 4.4. uPAR Stimulation of Plasminogen Activation.- 4.4.1. uPA and the Template Mechanism.- 4.4.2. Plasminogen and the Template Mechanism.- 4.5. Avian uPA, a Special Case?.- 5. Tissue Plasminogen Activator, tPA.- 5.1. Serine Protease Domain.- 5.2. N-terminal Domains.- 5.2.1. KR Modules.- 5.2.2. Fl-EG Supermodule.- 6. Mechanisms Regulating tPA Function.- 6.1. Zymogenicity.- 6.2. Fibrin Stimulation of Plasminogen Activation.- 6.2.1. tPA/fibrin Interaction.- 6.2.2. Vampire Bat Plasminogen Activator.- 6.3. Cellular Mechanisms Regulating tPA Activity.- 6.3.1. Endothelial Cells.- 6.3.2. Vascular Smooth Muscle Cells.- 6.3.3. Prion Protein.- 7. Concluding Remarks.- References.- 3. Plasminogen Activators Inhibitors.- 1. Plasminogen Activator Inhibitor-1.- 1.1. Natural and Recombinant PAI-1.- 1.2. Distinct Conformations of PAI-1.- 1.3. Target Specificity of PAI-1.- 1.4. PAI-1 in Patho-Physiological Processes.- 1.4.1. PAI-1 and Cardiovascular Disease.- 1.4.2. PAI-1 and Cancer.- 1.5. PAI-1 Inhibitors and their Binding Sites.- 2. Plasminogen Activator Inhibitor-2.- 2.1. Function of PAI-2.- 2.2. PAI-2 Polymerization.- 3. Plasminogen Activator Inhibitor-3.- 3.1. Target Specificity of PAJ-3.- 3.2. Physiological Role of PAI-3.- References.- 4. Regulation of Plasminogen Gene Expression.- 1. Introduction.- 2. The Plasminogen Gene.- 2.1. Mechanisms of Constitutive Regulation of Plasminogen Gene Expression.- 2.2. Plasminogen Distribution in Tissues.- 3. Regulation of Plasminogen Gene Expression in vitro and in vivo.- 3.1. Interleukin-6.- 3.2. Glucocorticoids.- 3.3. LPS.- 3.4. Tumor Necrosis Factor-? (TNF-?) and Transforming Growth Factor-? (TGF-?).- 3.5. Interleukin-1.- 3.6. Kainic Acid.- 4. Conclusions.- Acknowledgments.- References.- 5. Plasminogen Receptors.- 1. Introduction to Cellular Plasminogen Activation.- 2. Mechanism of Cellular Plasminogen Binding.- 2.1. History.- 2.2. Kinetics of Plasminogen Binding.- 2.3. Binding of Plasminogen Isoforms.- 3. Plasminogen Receptors as Regulators of Plasmin Activity.- 4. Modulation of Receptor Expression.- 4.1. Plasminogen Receptor Expression on Platelets.- 4.2. Plasminogen Receptor Expression on Endothelial Cells.- 4.3. Plasminogen Receptor Expression on Peripheral Blood Cells.- 4.4. Plasminogen Receptor Expression on Tumor Cells.- 5. Candidate Plasminogen Receptors.- 6. Annexin II, P11, and Annexin II Heterotetramer as Candidate Plasminogen Receptors.- 7. Concluding Remarks.- References.- 6. The Role of Lys-Plasminogen in Cell-Mediated Plasmin Production.- 1. Introduction.- 2. Key Differences between Glu-Plasminogen and Lys-Plasminogen.- 3. Mechanisms by which Plasminogen Activation is Enhanced on the Cell Surface.- 3.1. Role of the Glu-Plasminogen to Lys-Plasminogen Conversion in Plasminogen Activation by t-PA on the Cell Surface.- 3.2. Role of the Glu-Plasminogen to Lys-Plasminogen Conversion in Plasminogen Activation by u-PA on the Cell Surface.- 3.3. Effect of Cells on Conversion of [D(646)E]Glu-Pg to [D(646)E]Lys-Pg by Exogenous Plasmin.- 4. Conclusions.- Acknowledgments.- References.- 7. Plasmin Reductase.- 1. Introduction.- 2. Identification of Plasmin Reductase Activity.- 3. Disulfide-Bonds Cleaved by Plasmin Reductase.- 4. Proteolysis of Reduced Plasmin.- 5. Plasmin Reductase is Phosphoglycerate Kinase.- 6. Structure/Function Aspects of Plasmin Reduction by Phosphoglycerate Kinase.- 7. Putative Mechanism of Action of Phosphoglycerate Kinase.- 8. Phosphoglycerate Kinase in Tumor Angiogenesis.- 9. Future Directions.- References.- 8. Mechanism of Angiostatin Formation from Plasminogen.- 1. Introduction.- 2. Identification of Plasminogen Fragment, A61, Produced by Plasmin Autoproteolysis.- 3. Characterization of A61, an Anti-Angiogenic Plasminogen Fragment.- 4. Identification of Cell-Generated Plasminogen Fragments.- 5. Characterization of p22, the Smallest Anti-Angiogenic Plasminogen Fragment Produced by Cultured Cells.- 6. Identification of Plasminogen Fragments Present in Sera.- 7. Annexin II Tetramer, a Putative Plasminogen Receptor.- 8. Plasmin Reductase Activity of Annexin II Tetramer.- 9. Mechanism of Action of Annexin II Tetramer on A61 Formation.- 10. Concluding Remarks.- Acknowledgment.- References.- II. Physiological Roles of Plasminogen.- 9. Lessons Learned from the Pig Deficient Mice (Plg-/-).- 1. Introduction.- 2. Development.- 2.1. Physical Development.- 2.2. Behavioral Development.- 3. Role of the Plg System in Stress.- 3.1. Alterations of the Plg System in Response to Stress.- 3.2. Grooming, a Stress-Induced Behavior is Increased in the Plg-/- Mice.- 3.3. Acoustic Startle Reflex, a Stress-Induced Behavior is Decreased in Plg-/- Mice.- 3.4. The Plg System in Neuroendocrine Tissues and Alterations in Plg-/- Mice.- 4. Role of the Plg System in Adipose Tissue Development.- 4.1. Role of the Plg System in Obesity.- 4.2. Plg and Plg System Components in Adipose Tissue.- 4.3. Adipose Tissue Development in Plg-/- Mice.- 4.4. Vascularization of Adipose Tissue.- 5. Summary.- References.- 10. Plasminogen-Directed Phenotypes in Mice.- 1. Introduction.- 2. Generation and Initial Characterization of Plasminogen-Deficient Mice (PG-/-).- 3. Challenge-Induced Phenotypes in Mice Deficient for Plasminogen.- 3.1. Pulmonary Clot Lysis.- 3.2. Responses to Vascular Injury.- 3.3. Pathogen Susceptibility and Inflammation.- 3.4. Glomerulonephritis.- 3.5. Rheumatoid Arthritis.- 3.6. Pulmonary Fibrosis.- 3.7. Wound Healing.- 3.8. Neuronal and Axonal Degeneration and Demyelination.- 3.9. Tumor Development, Metastatis, and Angiogenesis.- 4. Conclusion.- References.- 11. Role of the Plasminogen and MMP Systems in Wound Healing.- 1. Introduction.- 2. Plasminogen/Plasmin and MMP Systems.- 2.1. Plasminogen/Plasmin System.- 2.2. MMP System.- 2.3. Molecular Interactions Between the Plasminogen/Plasmin and MMP Systems.- 3. Arterial Restenosis.- 3.1. Role of the Plasminogen/Plasmin System in Neointima Formation.- 3.2. Role of the MMP System in Neointima Formation.- 4. Allograft Transplant Stenosis.- 5. Skin Wound Healing.- 6. Myocardial Ischemia.- 7. Summary.- References.- 12. Matrix Metalloproteinases and the Plasminogen System in Tumor Progression.- 1. Introduction.- 2. Matrix Metalloproteinases.- 2.1. MMP Classification and their Expression in Cancer.- 2.2. Substrate Specificity.- 2.3. Activation.- 3. Interactions Between MMPs and the Plasminogen System.- 3.1. Activation of proMMPs by Plasmin.- 3.2. Cleavage of Plasmin by MMPs.- 3.3. MMPs Degrade Plasmin Inhibitors.- 3.4. MMPs and Plasmin Degrade Several Common Proteins.- 4. Interaction between MMPs and the Plasminogen System in Tumor Invasion and Metastasis.- 4.1. Expression of MMPs and PA in Cancer.- 4.2. MMPs and Plasminogen Interactions in vitro.- 4.3. MMPs and Plasminogen Interaction in vivo.- 4.4. Conclusion and Directions.- 5. Interaction between MMPs and Plasminogen System in Angiogenesis.- 5.1. In vitro and in vivo Studies.- 5.2. Paradoxical Aspects.- 6. Relevance of these Studies in Human Cancer.- Acknowledgments.- References.- 13. Role of Plasminogen Activation in Hematopoietic Malignancies and in Normal Hematopoiesis.- 1. Introduction.- 2. Normal Hematopoiesis and its Control.- 3. Leukemia.- 3.1. Classification.- 3.2. Clinical Findings.- 4. Plasminogen Activation System in General.- 4.1. Structure and General Function of uPAR.- 4.2. Soluble uPAR (suPAR).- 5. Plasminogen Activation in Leukemia.- 5.1. Components of the PA System in Normal Blood Cells.- 5.2. Components of the PA System in Leukemia Cells.- 5.3. Soluble uPA and uPAR in Leukemia.- 5.4. Expression Patterns of uPAR Fragments in Leukemia Patients and in Healthy Controls.- 6. Clinical Impact of Plasminogen Activation in Leukemia.- 6.1. Plasminogen Activation System and Hemostasis.- 6.2. Cell Surface Plasminogen Activators and Urokinase Receptor: Diagnostic and Prognostic Tools in Leukemia?.- 6.3. suPAR as a Marker for Prognosis in Leukemia.- 7. Perspectives.- References.- 14. The Role of Plasminogen in Bone Remodeling.- 1. Osteoblasts and Bone Formation.- 2. Osteoclasts and Bone Resorption.- 3. Bone Remodeling.- 4. Regulation of the PA/Plasmin System in Bone Cells.- 4.1. Peptide Hormones and Cyclic AMP.- 4.2. Glucocorticoids and l,25(OH)2 Vitamin D3.- 4.3. Cytokines and Growth Factors.- 5. Potential Roles of the PA/Plasmin System in Bone.- 5.1. Bone Resorption.- 5.2. Studies in Genetically Manipulated Mice.- 5.3. Bone Formation.- References.- 15. Plasminogen Activators in CNS Physiology and Disease.- 1. Introduction.- 2. Expression and Function of Plasminogen Activators in the Normal CNS.- 2.1. Plasminogen Activators in Developing and Adult CNS.- 2.2. Role of Plasminogen Activators in Neuronal Migration, Plasticity, and Learning.- 2.2.1. Neuronal Migration.- 2.2.2. Synaptic Plasticity.- 3. Plasminogen Activators in CNS Pathologies.- 3.1. Excitotoxicity.- 3.2. Ischemic Stroke.- 3.3. Neurodegenerative Diseases.- 3.3.1. Alzheimer's Disease.- 3.3.2. Creutzfeldt-Jakob Disease.- 3.4. Neuroinflammatory Diseases.- 3.5. CNS Malignancy.- 4. Conclusions and Future Perspectives.- 5. Acknowledgments.- References.- 16. Role of the Plasminogen Activator-Plasmin System in Angiogenesis.- 1. Introduction.- 2. Role of the PA-Plasmin System in Angiogenesis.- 2.1. uPA/uPAR Interactions are Required for Angiogenesis.- 2.2. PAI-1 is Required for Angiogenesis.- 2.3. Does tPA Play a Role in Angiogenesis?.- 2.4. MMP Requirement for Fibrinolysis During Angiogenesis.- 2.5. Angiostatin and other Angiostatic Derivatives of Plasminogen.- 3. Requirement for the PA-Plasmin Systems in Polyoma Virus Middle T Oncogene-induced Vascular Tumor Formation.- 4. Conclusions and Perspectives.- Acknowledgments.- References.