Plasminogen: Structure, Activation, and Regulation

TheobservationthatabloodclotspontaneouslydissolveswasfirstdescribedbyDenys in1889. Subsequently,thebloodclottingsystemwasshowntobeinvolvedintumor growth. Forexample,asearlyas1925,Fisherreportedthataviantissueexplantstrans­ formedtomalignancybyvirusesgeneratedhighlevelsoffibrinolyticactivityundercon­ ditionsinwhichculturesofnormalcellsdidnot. In1958,theconceptthatan equilibriumexistedbetweenthetendencyofbloodtoclotandtoremainfluidwaspro­ posedbyAstrup. Atthattime,itwasbelievedthatthishemostaticbalancewasexplained bytheabilityofpolymerizingfibrintoorchestrateitsownclearancebystimulatingfib­ rinolyticactivity. Sincethesepioneeringstudies,considerableinformationhasaccumu­ latedthathasdefinedthecomponentsofthecoagulationandfibrinolyticsystemsand howtheyareinvolvedinphysiologicalandpathophysiologicalprocesses. Plasminogen: Structure, activation, and regulationfocusesonthebasicprinciplesandrecentdevelop­ mentsintheplasminogen/plasminresearchfieldandhowtheseresultsprovideacon­ ceptualframeworkforanunderstandingofthephysiologicalroleofplasminogenin healthanddisease. Theenzymaticcascadetriggeredbyactivationofplasminogenhasbeenimplicated inavarietyofnormalandpathologicaleventssuchasfibrinolysis,woundhealing,tis­ sueremodeling,embryogenesis,angiogenesis,andtheinvasionandmetastasisoftumor cells. Thisimpressivelistofphysiologicalfunctionsforplasminogenreinforcesthewide diversityofrolesthatplasminogenplaysinvariousphysiologicalprocesses. Productive plasmingenerationrequirestheassemblyofbothplasminogenactivatorsandplasmino­ genonasolidsupportsuchasthefibrinpolymerorthecellsurface. Theregulationof plasminproductioninvolvesacomplexinterplaybetweentheseplasminogenactivators, plasminogenactivatorinhibitors,andplasmininhibitors. Clearly,theexplosivegrowth 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-typePlasminogenActivator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3. 1. 2. Tissue-typePlasminogenActivator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3. 2. ActivationbyBacterial-derivedPlasminogenActivators. . . . . . . . . . . . . . . . . . . . . 9 3. 2. 1. Streptokinase 9 3. 2. 2. Staphylokinase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4. TargetsforPlasminActivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5. DysplasminogenemiasandPhenotypicManifestations 10 6. Conclusions 11 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2. Plasminogen Activators: Structure and Function Vincent Ellis 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2. SerineProteases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3. UrokinasePlasminogenActivator,uPA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 3. 1. SerineProteaseDomain 22 3. 2. N-terminalDomains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 3. 2. 1. KRModule 24 3. 2. 2. EGModule 24 4. MechanismsRegulatinguPAFunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4. 1. ZymogenActivation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4. 2. ZymogenActivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4. 3. ReciprocalZymogenActivation 27 4. 4. uPARStimulationofPlasminogenActivation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4. 4. 1. uPAandtheTemplateMechanism 28 4. 4. 2. PlasminogenandtheTemplateMechanism 29 4. 5. AvianuPA,aSpecialCase? 30 xiii xiv Contents 5. TissuePlasminogenActivator,tPA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5. 1. SerineProteaseDomain 31 5. 2. N-terminalDomains ,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5. 2. 1. KRModules ,. . ,. . ,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5. 2. 2. F1-EGSupermodule 33 6.