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书名: Handbook of Cell Signaling
作者: Bradshaw, Ralph A.; Dennis, Edward A.
出版时间: 2009-11-03
ISBN: 9780123741455(P-ISBN) ,9780080920917(O-ISBN)
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e9780123741455v1Front CoverHandbook of Cell SignalingCopyright PageContentsContributorsPreface to the Second EditionPreface to the First EditionChapter 1. Cell Signaling: Yesterday, Today, and TomorrowORIGINS OF CELL SIGNALINGENTER POLYPEPTIDE GROWTH FACTORSCELL SIGNALING AT THE MOLECULAR LEVELLIPID SIGNALINGCELL SIGNALING TOMORROWREFERENCESPart I: Initiation: Extracellular and Membrane EventsINTRODUCTIONSection A – Molecular RecognitionChapter 2. Structural and Energetic Basis of Molecular RecognitionINTRODUCTIONPRINCIPLES OF BINDINGNON-SPECIFIC ASSOCIATION WITH MEMBRANE SURFACESPROTEIN–PROTEIN INTERACTIONSPROSPECTSREFERENCESChapter 3. Free Energy Landscapes in Protein-Protein InteractionsTHERMODYNAMICS OF PROTEIN–PROTEIN INTERACTIONSINTERACTION KINETICSDISSOCIATION OF A PROTEIN COMPLEXTHE MODULAR STRUCTURE OF PROTEIN–PROTEIN BINDING SITESINTERACTION BETWEEN MEMBRANE-ANCHORED PROTEINSSUMMARYREFERENCESChapter 4. Molecular SociologyTRANSMEMBRANE SIGNALING PARADIGMSSTRUCTURAL BASIS OF PROTEIN–PROTEIN RECOGNITIONCONCLUSIONREFERENCESChapter 5. Antibody-Antigen Recognition and Conformational ChangesINTRODUCTIONANTIBODY ARCHITECTURECONFORMATIONAL CHANGESUNUSUAL STRUCTURAL MODIFICATIONSCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 6. Binding Energetics in Antigen-Antibody InterfacesINTRODUCTIONTHERMODYNAMIC MAPPING OF ANTIGEN–ANTIBODY INTERFACESCONCLUSIONSREFERENCESChapter 7. Immunoglobulin–Fc Receptor InteractionsINTRODUCTIONIMMUNOGLOBULIN STRUCTUREFc RECEPTORS AND THEIR STRUCTURESIgG–RECEPTOR INTERACTIONSIgE–RECEPTOR INTERACTIONSIgA–RECEPTOR INTERACTIONSCONCLUSIONSREFERENCESChapter 8. Ig-Superfold and its Variable Uses in Molecular RecognitionINTRODUCTIONTHE IMMUNOGLOBULIN SUPERFAMILYIG-SUPERFOLD-MEDIATED RECOGNITIONREFERENCESChapter 9. T Cell Receptor/pMHC ComplexesTCR GENERATION AND ARCHITECTUREPEPTIDE BINDING TO MHC CLASS IA AND IITCR/pMHC INTERACTIONORIENTATION OF THE TCR IN TCR/PMHC COMPLEXESPEPTIDE RECOGNITION BY THE TCR CDR LOOPSDISCREPANCY BETWEEN MAGNITUDE OF STRUCTURAL CHANGES AND BIOLOGICAL OUTCOMESROLE OF BOUND WATER IN TCR/pMHC RECOGNITIONCONCLUSIONS AND FUTURE PERSPECTIVESREFERENCESChapter 10. Mechanistic Features of Cell-Surface Adhesion ReceptorsMECHANOSENSORY MECHANISMSCELL–CELL ADHESIONS/ADHERENS JUNCTIONST CELL CO-STIMULATIONAXON GUIDANCE AND NEURAL DEVELOPMENTCONCLUSIONSREFERENCESChapter 11. The Immunological SynapseINTRODUCTIONMIGRATION AND THE ISTHE MEMBRANE–CYTOSKELETON COMPLEX AND THE ISREQUIREMENTS FOR TCR TRIGGERINGINTEGRATION OF ADAPTIVE AND INNATE RESPONSESROLE OF IS IN T CELL DIFFERENTIONSUMMARYACKNOWLEDGMENTSREFERENCESChapter 12. NK ReceptorsIMMUNORECEPTORSNATURAL KILLER CELLSIG-TYPE NK RECEPTORS: KIROTHER IG-TYPE RECEPTORS ON NK CELLSC-TYPE LECTIN-LIKE NK RECEPTORS: LY49AC-TYPE LECTIN-LIKE NK RECEPTORS: NKG2DREFERENCESChapter 13. Carbohydrate Recognition and SignalingINTRODUCTIONBIOLOGICAL ROLES OF CARBOHYDRATE RECOGNITIONCARBOHYDRATE STRUCTURE AND DIVERSITYLECTINS AND CARBOHYDRATE RECOGNITIONCARBOHYDRATE-MEDIATED SIGNALINGCONCLUSIONSREFERENCESChapter 14. Rhinovirus-Receptor InteractionsREFERENCESChapter 15. HIV-1–Receptor InteractionsMOLECULAR INTERACTIONSATOMIC DETAILSRECOGNITION IN THE CONTEXT OF A HUMORAL IMMUNE RESPONSEREFERENCESChapter 16. Influenza Virus Neuraminidase InhibitorsFLU VIRUS – ROLE OF NASTRUCTURE OF NAACTIVE SITEINHIBITOR DEVELOPMENTRESISTANCE MUTATIONSCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 17. Structural Basis of Signaling Events Involving Fibrinogen and FibrinSIGNALING EVENTS INVOLVING CELLS AND PLATELETSREFERENCESChapter 18. Structural Basis of Integrin SignalingINTRODUCTIONSTRUCTUREQUATERNARY CHANGESTERTIARY CHANGESTAIL INTERACTIONSCONCLUDING REMARKSREFERENCESChapter 19. Structures of Heterotrimeric G Proteins and their ComplexesINTRODUCTIONG SUBUNITSG-EFFECTOR INTERACTIONSGTP HYDROLYSIS BY G AND ITS REGULATION BY GAPsGβγ DIMERSRECEPTOR-INDEPENDENT REGULATORS OF G PROTEIN ACTIVATIONGα–GPCR INTERACTIONSREFERENCESChapter 20. G Protein-Coupled Receptor StructuresINTRODUCTIONCLASSIFICATIONBASIC CONCEPT OF GPCR; HETEROTRIMERIC G PROTEINS; THE VAST COMPLEXITY OF GPCR SIGNALINGMODELS FOR RECEPTOR ACTIVATIONSTRUCTURES OF EXTRACELLULAR DOMAINS OF GPCRsSTRUCTURES PROBING THE INACTIVE STATES): LIGAND ENTRY, BINDING, AND MODES FOR ACTIVITY BLOCKINGSTRUCTURE OF ACTIVE STATES)ACKNOWLEDGEMENTSREFERENCESChapter 21. Toll-Like Receptors–Structure and SignalingSTRUCTURE OF TLR3THE dsRNA BINDING SITE IN hTLR3TLR4MD-2TLR1–TLR2 DIMERIZATION BY A TRI-ACYLATED LIPOPEPTIDESIGNALINGACKNOWLEDGEMENTSREFERENCESChapter 22. Variable Lymphocyte ReceptorsINTRODUCTIONVLR GENE ASSEMBLYVLR-B ANTIBODY RESPONSESMONOCLONAL VLR-B ANTIBODIESSTRUCTURE OF VLR-B BINDING TO ANTIGENREFERENCESSection B – Multi-pass ReceptorsChapter 23. Structure and Function of G-Protein-Coupled Receptors: Lessons from Recent Crystal StructuresINTRODUCTIONRECENT ADVANCES IN STRUCTURAL STUDIES OF G-PROTEIN-COUPLED RECEPTORSCRYSTAL STRUCTURES OF HUMAN β[sub2)]ARUNDERSTANDING LIGAND BINDING SPECIFICITY IN GPCRsSTRUCTURAL BASIS OF THE ACTIVE STATEREFERENCESChapter 24. Chemokines and Chemokine Receptors: Structure and FunctionINTRODUCTIONCHEMOKINE STRUCTURE AND FUNCTIONCHEMOKINE RECEPTORSREFERENCESChapter 25. The β[sub2)] Adrenergic Receptor as a Model for G-Protein-Coupled Receptor Structure and Activation by Diffusible HormonesINTRODUCTIONA MODEL SYSTEM FOR GPCRS RECOGNIZING DIFFUSIBLE LIGANDSCONFORMATIONAL STATES ON THE PATHWAY TO ACTIVATIONCRYSTAL STRUCTURES OF THE HUMAN β[sub2)]ARCOMPARISON TO THE STRUCTURE OF RHODOPSINMECHANISM OF AGONIST-INDUCED ACTIVATIONREFERENCESChapter 26. Protease-Activated ReceptorsINTRODUCTIONMECHANISM OF ACTIVATIONPROTEASE-ACTIVATED RECEPTOR FAMILYROLES OF PARs IN VIVOREFERENCESChapter 27. Agonist-Induced Desensitization and Endocytosis of G-Protein-Coupled ReceptorsGENERAL PROCESSES OF GPCR REGULATIONMECHANISMS OF GPCR DESENSITIZATION AND ENDOCYTOSISFUNCTIONAL CONSEQUENCES OF GPCR ENDOCYTOSISREFERENCESChapter 28. Functional Roles) of Dimeric Complexes Formed from G-Protein Coupled-ReceptorsINTRODUCTIONHISTORICAL PERSPECTIVEHETERODIMERIZATION ALTERS RECEPTOR FUNCTIONRECEPTOR HETERODIMERIZATION IN PHYSIOLOGY AND PATHOLOGYCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 29. Chemotaxis Receptors in Bacteria: Transmembrane Signaling, Sensitivity, Adaptation and Receptor ClusteringSIGNALING AT PERIPLASMIC LIGAND BINDING DOMAINSIGNALING AT THE CYTOPLASMIC DOMAINADAPTATIONCLUSTERING OF THE CHEMORECEPTOR AND SENSITIVITYFUTURE STUDIESACKNOWLEDGEMENTREFERENCESChapter 30. An Overview of Ion Channel StructureINTRODUCTIONOBTAINING THREE-DIMENSIONAL STRUCTURES OF CHANNELS: METHODS AND CHALLENGESPROKARYOTIC ION CHANNELS: GATEWAYS TO FULL LENGTH CHANNEL STRUCTUREOPEN CHANNELSEUKARYOTIC ION CHANNELS AT HIGH RESOLUTION: WHOLE CHANNELS AND EXPLOITATION OF MODULAR STRUCTURE TO DIVIDE AND CONQUERDIVIDE AND CONQUER: EXPLOITATION OF THE MODULAR NATURE OF ION CHANNEL STRUCTUREION CHANNEL COMPLEXESREFERENCESChapter 31. Molecular Mechanism of Store-Operated Ca[sup2+)] Signaling and CRAC Channel Activation Mediated by STIM & OraiINTRODUCTIONCRAC CHANNEL BIOPHYSICAL PROPERTIESSTIM SENSES ER CA[sup2+)] STORE DEPLETION, AGGREGATES, AND TRANSLOCATES TO ER–PLASMA MEMBRANE JUNCTIONSORAI FORMS THE CA[sup2+)]-SELECTIVE PORE OF THE CRAC CHANNELSTIM-INDUCED ACTIVATION OF ORAI CHANNELSREFERENCESChapter 32. Ion Permeation: Mechanisms of Ion Selectivity and BlockAQUEOUS POREION SELECTIVITYBLOCKSUMMARYREFERENCESChapter 33. Nicotinic Acetylcholine ReceptorsFUNCTIONSTRUCTUREREFERENCESChapter 34. Ion Channels Regulated by Direct Binding of Cyclic NucleotidesINTRODUCTION6TM-CNB CHANNEL ARCHITECTURERECEPTOR DOMAINPORE DOMAINVOLTAGE-SENSING DOMAINREFERENCESSection C – Horizontal ReceptorsChapter 35. Overview of Cytokine ReceptorsChapter 36. Growth Hormone and Prolactin Family of Hormones and Receptors: The Structural Basis for Receptor Activation and RegulationINTRODUCTIONTHE GROWTH HORMONE FAMILY OF HORMONES AND RECEPTORSTRIGGERING GH AND PRL RECEPTOR ACTIVATION: REVISION TO THE DOGMAAN UNANTICIPATED ROLE FOR CYTOKINE HORMONES AS TRANSCRIPTIONAL ENHANCERSSTRUCTURAL BASIS FOR RECEPTOR HOMODIMERIZATIONHORMONE SPECIFICITY AND CROSS-REACTIVITY DETERMINES PHYSIOLOGICAL ROLESCONCLUDING REMARKSREFERENCESChapter 37. Erythropoietin Receptor as a Paradigm for Cytokine SignalingINTRODUCTIONSTRUCTURAL STUDIES ON EPORBIOCHEMICAL STUDIES SUPPORTING PREFORMED DIMERSOTHER CYTOKINE RECEPTOR SUPERFAMILY MEMBERSCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 38. The Fibroblast Growth Factor FGF) Signaling ComplexINTRODUCTIONFGF POLYPEPTIDESFGFR TYROSINE KINASESHEPARAN SULFATE AND KLOTHOSTHE OLIGOMERIC FGF–FGFR–HS SIGNALING COMPLEXINTRACELLULAR SIGNAL TRANSDUCTION BY THE FGFR COMPLEXREFERENCESChapter 39. Structure of IFNγ and its ReceptorsREFERENCESChapter 40. Structure and Function of Tumor Necrosis Factor TNF) at the Cell SurfaceINTRODUCTIONSTRUCTURAL FEATURESSIGNALING PATHWAYS AND REGULATIONBIOLOGICAL FUNCTIONSTHERAPEUTICS AND FUTURE EXPECTATIONSACKNOWLEDGEMENTREFERENCESChapter 41. The Mechanism of NGF Signaling Suggested by the p75 and TrkA Receptor ComplexesINTRODUCTIONNEUROTROPHINSNGF–TrkA COMPLEXESNGF–p75[supNTR)] COMPLEXESNEUROTROPHIN SIGNALING EXCURSIONSPROSPECTS FOR TERNARY RECEPTOR COMPLEXESNEUROTROPHIN THERAPEUTICSREFERENCESChapter 42. The Mechanism of VEGFR Activation by VEGFSTRUCTURAL CHARACTERIZATION OF VEGF FAMILY MEMBERSSTRUCTURAL CHARACTERIZATION OF VEGFRsPDGFR AND ANALOGIES TO VEGFRsVEGF CO-RECEPTORS: NEUROPILINSCONCLUSIONREFERENCESChapter 43. Receptor-Ligand Recognition in the TGFβ Superfamily as Suggested by Crystal Structures of their Ectodomain ComplexesINTRODUCTIONLIGAND STRUCTURESRECEPTOR STRUCTURESRECEPTOR–LIGAND COMPLEXESCONCLUDING REMARKSNOTESREFERENCESChapter 44. Insulin Receptor Complex and Signaling by InsulinINTRODUCTIONINSULIN RECEPTOR DOMAIN STRUCTUREBINDING DETERMINANTS OF THE INSULIN RECEPTORINSULIN SIGNALING TO GLUCOSE TRANSPORTACKNOWLEDGEMENTSREFERENCESChapter 45. Structure and Mechanism of the Insulin Receptor Tyrosine KinaseINTRODUCTIONPROTEIN RECRUITMENT TO THE ACTIVATED INSULIN RECEPTORPROSPECTSACKNOWLEDGEMENTSREFERENCESChapter 46. IL-21 Increased Potency DesignINTRODUCTIONGROWTH HORMONE hGH)RATIONAL DESIGN – IL-21SECONDARY STRUCTURE COMPARISON OF hIL-4, hIL-21, AND CHIM-hIL-21/4ORIGIN OF OBSERVED SUPERPOTENCY FOR CHIM-hIL-21/4CONCLUSIONREFERENCESChapter 47. Signaling of IL-4R, a Typical Class I Cytokine Receptor: What Defines the Quiescent State?INTRODUCTIONCLASS I CYTOKINE RECEPTORS: A GRAMMAR OF LONG AND SHORTLIGAND-INDUCED DIMERIZATIONSTRUCTURE–FUNCTION RELATIONSHIPS WITHIN THE IL-4R ECDA MEMBRANE-DEPENDENT ACTIVATION MODELCONCLUSIONREFERENCESChapter 48. Epidermal Growth Factor Kinases and their Activation in Receptor Mediated SignalingINTRODUCTIONEGFR SIGNALING NETWORK PATHWAYSSTRUCTURAL BIOLOGY OF RECEPTOR FRAGMENTSCONFORMATIONS OF THE ECD FRAGMENTS OF ErbB RECEPTORSKINASE DOMAIN FRAGMENT STRUCTURESBIOPHYSICAL STUDIES OF ErbB ACTIVATION AT THE CELL SURFACEErbB RECEPTORS EXIST AS PREDOMINANTLY PRE-FORMED DIMERS IN CELLSBEYOND DIMERS: A LIGAND-INDUCED EGFR TETRAMER IS FORMED DURING ACTIVATIONACTIVATION-DEPENDENT HIGHER-ORDER ErbB OLIGOMERS IN CANCER CELLSNEW PARADIGM IN ErbB ACTIVATION AND SIGNALINGREFERENCESSection D – Membrane Proximal EventsChapter 49. Tumor Necrosis Factor Receptor-Associated Factors in Immune Receptor Signal TransductionINTRODUCTIONDISCOVERY OF TRAF PROTEINSBIOLOGICAL FUNCTIONS OF TRAF PROTEINSDOMAIN ORGANIZATIONS AND STRUCTURES OF TRAFsTHE UNIQUE TRAF6TRAF SIGNALING AND LYS63 LINKED POLYUBIQUITINATIONREGULATION OF TRAF SIGNALINGSUMMARY AND PERSPECTIVESACKNOWLEDGEMENTREFERENCESChapter 50. Assembly of Signaling Complexes for TNF Receptor Family MoleculesINTRODUCTIONRECEPTOR AGGREGATIONRAFT RECRUITMENTUBIQUITINATIONRECEPTOR INTERACTIONSINTERACTIONS WITH TRAFSCONCLUSIONSREFERENCESChapter 51. Mechanisms of CD40 Signaling the Immune SystemINTRODUCTIONTHE SIGNALING CASCADE TRIGGERED BY CD40CD40 SIGNALING IS MEDIATED BY TRAF-DEPENDENT AND TRAF-INDEPENDENT PATHWAYSREFERENCESChapter 52. Role of Lipid Domains in EGF Receptor SignalingINTRODUCTIONSTUDYING LIPID RAFTSLOCALIZATION OF THE EGF RECEPTOR IN LIPID RAFTSRAFTS AND EGF RECEPTOR-MEDIATED SIGNALINGTHE EGF RECEPTOR AND CAVEOLINREFERENCESChapter 53. Lipid-Mediated Localization of Signaling ProteinsINTRODUCTIONLIPID MODIFICATIONS ON THE CYTOPLASMIC FACE OF MEMBRANESLIPID MODIFICATIONS IN THE LUMEN OF THE SECRETORY PATHWAYLOCALIZATION OF LIPID-MODIFIED PROTEINSSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 54. Organization of Photoreceptor Signaling ComplexesINTRODUCTIONINAD ORGANIZES SIGNALING COMPLEXES IN PHOTORECEPTORSTHE ROLE OF INAD-SIGNALING COMPLEXES IN PHOTOTRANSDUCTIONASSEMBLY, TARGETING, AND ANCHORING OF SIGNALING COMPLEXESREFERENCESChapter 55. Transmembrane Receptor OligomerizationINTRODUCTIONTYROSINE KINASE-CONTAINING RECEPTORSCYTOKINE RECEPTORSGUANYLYL CYCLASE-CONTAINING RECEPTORSSERINE/THREONINE KINASE-CONTAINING RECEPTORSTUMOR NECROSIS FACTOR RECEPTORSHEPTAHELICAL RECEPTORS G-PROTEIN-COUPLED RECEPTORS)CONCLUDING REMARKSREFERENCESe9780123741455v2Front CoverHandbook of Cell SignalingCopyright PageContentsContributorsPreface to the Second EditionPreface to the First EditionPart II: Transmission: Effectors and Cytosolic EventsINTRODUCTIONSection A – Protein PhosphorylationChapter 56. Eukaryotic Kinomes: Genomics and Evolution of Protein KinasesINTRODUCTIONTHE HUMAN KINOMECOMPARATIVE KINOMICSEMERGENCE AND DIVERSITY OF VERTEBRATE KINOMESCODAREFERENCESChapter 57. Modular Protein Interaction Domains in Cellular CommunicationINTRODUCTIONPHOSPHOTYROSINE-DEPENDENT PROTEIN–PROTEIN INTERACTIONSINTERACTION DOMAINS: A COMMON THEME IN SIGNALINGADAPTORS, PATHWAYS, AND NETWORKSINTERACTION DOMAINS IN THE EVOLUTION OF SIGNALING PATHWAYSEMERGENT PROPERTIES OF MODULAR PROTEIN INTERACTION DOMAIN-DRIVEN SIGNALING NETWORKSACKNOWLEDGEMENTSREFERENCESChapter 58. Structures of Serine/Threonine and Tyrosine KinasesINTRODUCTIONSTRUCTURAL FEATURES OF SERINE/THREONINE AND TYROSINE KINASESREGULATION OF SERINE/THREONINE AND TYROSINE KINASE ACTIVITYPROSPECTSACKNOWLEDGEMENTSREFERENCESChapter 59. Protein Tyrosine Kinase Receptor Signaling OverviewINTRODUCTIONPTK SUBFAMILIESMECHANISM OF ACTIVATIONCONTROL OF PTK RECEPTOR ACTIVITYCROSS-TALK BETWEEN SIGNALING PATHWAYSPTK RECEPTORS AND DISEASEACKNOWLEDGEMENTSREFERENCESChapter 60. Signaling by the Platelet-Derived Growth Factor Receptor FamilyPLATELET-DERIVED GROWTH FACTOR ISOFORMSPHYSIOLOGICAL FUNCTION OF PDGFACTIVATION OF PLATELET-DERIVED GROWTH FACTOR RECEPTORS AND REGULATION OF KINASE ACTIVITYINTERACTION OF THE PDGF RECEPTORS WITH DOWNSTREAM SIGNAL TRANSDUCTION MOLECULESREGULATION AND MODULATION OF PDGF RECEPTOR SIGNALINGCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 61. The Epidermal Growth Factor Receptor FamilyINTRODUCTIONSTRUCTURE AND ACTIVATION OF ERBB RECEPTORS AND THEIR LIGANDSERBB-INDUCED SIGNALING PATHWAYSSPECIFICITY OF SIGNALING THROUGH THE ERBB NETWORKATTENUATION OF THE ERBB SIGNALING NETWORKERBB PROTEINS AND PATHOLOGICAL CONDITIONSACKNOWLEDGEMENTSREFERENCESChapter 62. Mechanisms and Functions of Eph Receptor signalingINTRODUCTIONEPH/EPHRIN PROTEIN STRUCTURES AND SIGNALING CONCEPTSREGULATION OF EPH/EPHRIN SIGNALING ACTIVITYDISRUPTION OF CELL–CELL CONTACTS AND INTERNALIZATION OF SIGNALING COMPLEXESEPH FORWARD) SIGNALINGEPHRIN REVERSE) SIGNALINGCROSS-TALK WITH OTHER SIGNAL PATHWAYSEPH/EPHRIN FACILITATED CELL-CELL COMMUNICATION DURING VERTEBRATE DEVELOPMENTEPHS IN ONCOGENESIS: DE-REGULATED CELL POSITIONING DURING INVASION AND METASTASISREFERENCESChapter 63. Cytokine Receptor SignalingINTRODUCTIONGENERATION OF HIGH-AFFINITY CYTOKINE–RECEPTOR COMPLEXESARCHITECTURE OF EXTRACELLULAR DOMAINRECEPTOR SIGNALING-UTILIZING EPO-R AS A MODELACTIVATION OF THE JAK TYROSINE KINASESJAK1JAK2JAK3TYK2RECRUITMENT AND ACTIVATION OF STAT TRANSCRIPTION FACTORSSTAT1STAT2STAT3STAT4STAT5STAT6PARTICIPATION OF THE PHOSHATIDYLINOSITOL 3 KINASE PATHWAY IN CELL SURVIVAL SIGNALINGERK, JNK AND P38 ARE ALL ACTIVATED DOWNSTREAM OF CYTOKINE RECEPTOR ENGAGEMENTNEGATIVE REGULATIONDEVELOPMENTAL REGULATION OF THE CYTOKINE SIGNALING PATHWAYINVOLVEMENT OF THE CYTOKINE SIGNALING PATHWAY IN HUMAN DISEASECONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 64. The Negative Regulation of JAK/STAT signalingINTRODUCTIONMODULATION OF JAK KINASE ACTIVITY BY EXTRINSIC KINASESPROTEIN INHIBITORS OF ACTIVATED STATS PIAS)SUPPRESSORS OF CYTOKINE SIGNALINGFUTURE OUTLOOKACKNOWLEDGEMENTSREFERENCESChapter 65. Protein Kinase InhibitorsSIGNAL TRANSDUCTION THERAPY AND PROTEIN KINASE INHIBITORSPROTEIN TYROSINE KINASE INHIBITORSSER/THR KINASE INHIBITORSREFERENCESChapter 66. Integrin Signaling: Cell Migration, Proliferation, and SurvivalINTRODUCTIONINTEGRINS NUCLEATE THE FORMATION OF DYNAMIC MULTI-PROTEIN COMPLEXESCELL MIGRATION: A PARADIGM FOR STUDYING INTEGRIN SIGNALINGLAMELLIPODIA EXTENSION, AND ADHESION FORMATION AND STABILIZATION AT THE LEADING EDGEMATURATION, DETACHMENT, AND RELEASE OF ADHESIONSGROWTH FACTOR RECEPTOR AND INTEGRIN SIGNALING-SYNERGISTIC REGULATION OF CELL PROLIFERATION AND SURVIVALINTEGRIN SIGNALS AND LINKS TO CANCERCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 67. Downstream Signaling Pathways: Modular InteractionsINTRODUCTIONGENERAL PROPERTIES OF INTERACTION MODULESROLES IN SIGNALINGPROSPECTSREFERENCESChapter 68. Non-Receptor Tyrosine Kinases in T Cell Antigen Receptor FunctionINTRODUCTIONT CELL ANTIGEN RECEPTOR SIGNALINGSRC FAMILY KINASESCSKZAP-70TEC KINASESCONCLUSIONSREFERENCESChapter 69. Receptor Tyrosine Kinase Signaling and UbiquitinationINTRODUCTIONTHE UBIQUITIN CONJUGATION SYSTEMRTK SIGNALING AND ENDOCYTOSIS ARE MOLECULARLY LINKEDUBIQUITINATION IN RTK ENDOCYTOSISUBIQUITINATION OF EFFECTOR PROTEINS IN RTK SIGNALINGCONCLUDING REMARKS AND FUTURE PERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 70. TGFγ Signal TransductionINTRODUCTIONTGFβ LIGANDSRECEPTORSACTIVATION AND REGULATION OF RECEPTORSTHE SMADS: EFFECTORS OF TGFβ FAMILY TRANSCRIPTIONAL PROGRAMSSMAD ACTIVATIONREGULATION OF TGFβ SIGNAL TRANSDUCTION BY INHIBITORY SMADSSMADS ARE DNA-BINDING PROTEINSSMADS COOPERATE WITH DNA-BINDING PARTNERSSMADS INTERACT WITH TRANSCRIPTION CO-ACTIVATORS AND REPRESSORSNON-SMAD SIGNALING PATHWAYSREFERENCESChapter 71. Mitogen-Activated Protein KinasesA BRIEF HISTORYCOMMON FEATURESMAMMALIAN MAPKSSAME PLAYERS, MULTIPLE ROLESSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 72. Recognition of Phospho-Serine/Threonine Phosphorylated Proteins by Phospho-Serine/Threonine-Binding DomainsINTRODUCTION14-3-3 PROTEINSFHA DOMAINSWW DOMAINSPOLO-BOX DOMAINSTANDEM BRCT-REPEAT DOMAINSLEUCINE-RICH REPEATS AND WD40 DOMAINSCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 73. AMP-Activated Protein KinaseINTRODUCTIONSTRUCTURE OF THE AMPK/SNF1 COMPLEXREGULATION OF THE AMPK COMPLEXREGULATION IN INTACT CELLS AND IN VIVODOWNSTREAM TARGETS FOR AMPKMEDICAL IMPLICATIONS OF THE AMPK SYSTEMACKNOWLEDGEMENTSREFERENCESChapter 74. Principles of Kinase RegulationINTRODUCTIONPROTEIN KINASE STRUCTUREGENERAL PRINCIPLES OF CONTROLREGULATORY SITES IN PROTEIN KINASE DOMAINSCONCLUSIONSREFERENCESChapter 75. Calcium/Calmodulin-Dependent Protein Kinase IIINTRODUCTIONSTRUCTURE OF CAMKIIREGULATION BY AUTOPHOSPHORYLATIONREGULATORY ROLES OF CAMKII IN NEURONSREFERENCESChapter 76. Glycogen Synthase Kinase 3INTRODUCTIONTHE SUBSTRATE SPECIFICITY OF GSK3THE REGULATION OF GSK3 ACTIVITY BY INSULIN AND GROWTH FACTORSGSK3 AS A DRUG TARGETTHE ROLE OF GSK3 IN EMBRYONIC DEVELOPMENTGSK3 AND CANCERACKNOWLEDGEMENTSREFERENCESChapter 77. The PIKK Family of Protein KinasesINTRODUCTIONOVERVIEW OF PIKK FAMILY MEMBERSOVERALL ARCHITECTURE OF PIKK FAMILY PROTEINSmTOR: A KEY REGULATOR OF CELL GROWTHDNA-PKCS: AT THE HEART OF THE DNA NON-HOMOLOGOUS END-JOINING MACHINERYATM AND ATR: SIGNALERS OF GENOME DAMAGESMG-1: A REGULATOR OF NONSENSE-MEDIATED MRNA DECAYTRRAP: A CRUCIAL TRANSCRIPTIONAL CO-ACTIVATORPIKK FAMILY MEMBERS AS GUARDIANS OF NUCLEIC ACID STRUCTURE, FUNCTION, AND INTEGRITY?ACKNOWLEDGEMENTSREFERENCESChapter 78. Histidine Kinases in Two-Component Signaling PathwaysINTRODUCTIONABUNDANCE AND EVOLUTIONARY DIVERSITY OF HKSDOMAIN ORGANIZATION AND FUNCTIONAL ACTIVITIES OF HKSHISTIDINE PHOSPHORYLATION AND REGULATION OF HKSINTERACTION WITH RESPONSE REGULATOR PROTEINSACKNOWLEDGEMENTSREFERENCESChapter 79. The EF2K/MHCK/TRPM7 Family of Atypical Protein KinasesIDENTIFICATION OF AN ATYPICAL FAMILY OF PROTEIN KINASES: EF2K, MHCK AND TRPM7THE STRUCTURE OF THE TRPM7 KINASE DOMAIN REVEALS SIMILARITY TO CLASSICAL PROTEIN KINASESSUBSTRATE RECOGNITION BY EF2K, TRPM7, AND MHCKSEF2K: REGULATION AND FUNCTIONTRPM7: A NOVEL ION CHANNEL THAT CONTAINS AN ATYPICAL KINASE DOMAINMYOSIN HEAVY CHAIN KINASES AND OTHER ATYPICAL KINASESREFERENCESChapter 80. The Leucine-Rich Repeat Receptor Protein Kinases of Arabidopsis thaliana – a Paradigm for Plant LRR ReceptorsINTRODUCTIONLRR RECEPTOR PROTEIN KINASES: THE GENOMIC POINT OF VIEWLRR RECEPTOR PROTEIN KINASES: THE FUNCTIONAL VIEWERECTACLAVATA 1HAESAPEPR1SUMMARYREFERENCESChapter 81. Engineering Protein Kinases with Specificity for Unnatural Nucleotides and InhibitorsACKNOWLEDGEMENTSREFERENCESChapter 82. Clinical Applications of Kinase Inhibitors in Solid TumorsINTRODUCTIONRATIONALE FOR KINASE INHIBITION IN THE TREATMENT OF SOLID TUMORSKINASE INHIBITION IN GASTROINTESTINAL STROMAL TUMORSKINASE INHIBITORS IN NON-SMALL CELL LUNG CANCEREGFR MUTATIONS IN LUNG CANCERKINASE INHIBITORS IN RENAL CELL CARCINOMAKINASE INHIBITORS IN OTHER SOLID TUMORSLESSONS LEARNED?GLOSSARYACKNOWLEDGEMENTSREFERENCESChapter 83. Ubiquitin-mediated Regulation of Protein Kinases in NFκB SignalingINTRODUCTIONTHE UBIQUITIN PATHWAYNFκB SIGNALINGUBIQUITIN-MEDIATED ACTIVATION OF PROTEIN KINASES IN THE IL-1R AND TLR PATHWAYSUBIQUITIN-MEDIATED REGULATION OF NFκB AND APOPTOSIS IN THE TNFα PATHWAYDE-UBIQUITINATION ENZYMES PREVENT PROTEIN KINASES ACTIVATION IN THE NFκB PATHWAYPOLYUBIQUITINATION REGULATES PROTEIN KINASE ACTIVATION IN DIVERSE NFκB PATHWAYSCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 84. Global Analysis of Phosphoregulatory NetworksINTRODUCTIONGLOBAL MAPPING OF PHOSPHORYLATIONGLOBAL IDENTIFICATION OF KINASE–SUBSTRATE PAIRSCONCLUSIONREFERENCESSection B – Protein DephosphorylationChapter 85. Phosphatase Families Dephosphorylating Serine and Threonine Residues in ProteinsCURRENT CLASSIFICATION OF PROTEIN SERINE/THREONINE PHOSPHATASESBACKGROUNDEVOLUTION AND CONSERVED FEATURES OF THE PPP FAMILYHOLOENZYME STRUCTURES OF PPP FAMILY MEMBERSCATALYTIC ACTIVITIES OF THE PPP FAMILY MEMBERSFUNCTIONS OF PPP FAMILY MEMBERSMEDICAL IMPORTANCE OF THE PPP FAMILYTHE PPM FAMILYTHE FCP FAMILYCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 86. The Structure and Topology of Protein Serine/Threonine PhosphatasesINTRODUCTIONPROTEIN SERINE/THREONINE PHOSPHATASES OF THE PPP FAMILYPROTEIN SERINE/THREONINE PHOSPHATASES OF THE PPM FAMILYCONCLUSIONSREFERENCESChapter 87. Naturally Occurring Inhibitors of Protein Serine/Threonine PhosphatasesINTRODUCTIONEFFECTS OF INHIBITORS IN CELL-BASED EXPERIMENTSTHE TOXINS BIND TO THE ACTIVE SITES OF PROTEIN PHOSPHATASESCHEMICAL SYNTHESIS OF PROTEIN PHOSPHATASE INHIBITORSMICROCYSTIN AFFINITY CHROMATOGRAPHY AND AFFINITY TAGGINGAVOIDING THE MENACE OF TOXINS IN THE REAL WORLD OUTSIDE THE LABORATORYACKNOWLEDGEMENTSREFERENCESChapter 88. Protein Phosphatase 1 Binding ProteinsINTRODUCTIONPROTEIN PHOSPHATASE 1 PP1)PP1 REGULATORY OR TARGETING SUBUNITSCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 89. Protein Serine/Threonine Phosphatase Inhibitors and Human DiseaseINTRODUCTIONENVIRONMENTAL TOXINS AS PHOSPHATASE INHIBITORSNEW INSIGHTS IN CELLULAR PHOSPHATASE INHIBITORSCELLULAR PHOSPHATASE INHIBITORS AND HUMAN DISEASECONCLUDING REMARKSREFERENCESChapter 90. CalcineurinINTRODUCTIONENZYMATIC PROPERTIESSTRUCTUREREGULATIONDISTRIBUTION AND ISOFORMSFUNCTIONSCONCLUSIONREFERENCESChapter 91. Protein Serine/Threonine-Phosphatase 2C PP2C)INTRODUCTIONPP2C FUNCTIONS CONSERVED IN BOTH LOWER AND HIGHER EUKARYOTESPP2C FUNCTIONS SPECIFIC IN HIGHER EUKARYOTESREFERENCESChapter 92. Approaches to the Identification of Protein Tyrosine Phosphatase SubstratesINTRODUCTIONPTP CATALYSIS AND SUBSTRATE-TRAPPING MUTANTSSUBSTRATE-TRAPPING METHODSCRITERIA AND CAVEATS FOR DEFINING PTP SUBSTRATESPTP SUBSTRATES AND BIOLOGYACKNOWLEDGEMENTSREFERENCESChapter 93. Inhibitors of Protein Tyrosine PhosphatasesINTRODUCTIONCOVALENT PTP MODIFIERSOXYANIONS AS PTP INHIBITORSNON-HYDROLYZABLE pTyr SURROGATES AS PTP INHIBITORSBIDENTATE PTP INHIBITORSOTHER PTP INHIBITORSCONCLUDING REMARKSACKNOWLEDGEMENTREFERENCESChapter 94. Regulating Receptor PTP ActivityINTRODUCTIONREGULATION BY DIMERIZATIONREGULATION BY PHOSPHORYLATIONREGULATION BY REVERSIBLE OXIDATIONREGULATION BY PROTEOLYTIC PROCESSINGREGULATION BY LIGANDSCONCLUSIONSREFERENCESChapter 95. CD45INTRODUCTIONSTRUCTUREFUNCTIONREGULATIONSYNOPSISACKNOWLEDGEMENTSREFERENCESChapter 96. Cell-Cycle Functions and Regulation of Cdc14 PhosphatasesINTRODUCTIONTHE CDC14 PHOSPHATASE SUBGROUP OF PTPsBUDDING YEAST CDC14 IS ESSENTIAL FOR EXIT FROM MITOSISFISSION YEAST CDC14 COORDINATES CYTOKINESIS WITH MITOSISPOTENTIAL CELL-CYCLE FUNCTIONS OF HUMAN CDC14A AND BREFERENCESChapter 97. MAP Kinase PhosphatasesINTRODUCTIONSER/THR PROTEIN PHOSPHATASES AND THE REGULATION OF MAPK ACTIVITYMAPK REGULATION BY CLASSICAL PROTEIN TYROSINE PHOSPHATASES PTPs)MAPK REGULATION BY DUAL-SPECIFICITY PROTEIN PHOSPHATASESMAMMALIAN DUAL-SPECIFICITY MAPK PHOSPHATASESSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 98. SH2 Domain-Containing Protein-Tyrosine PhosphatasesHISTORY AND NOMENCLATURESTRUCTURE, EXPRESSION, AND REGULATIONBIOLOGICAL FUNCTIONS OF SHPSSHP SIGNALING AND SUBSTRATESDETERMINANTS OF SHP SPECIFICITYSHPS AND HUMAN DISEASESUMMARY AND FUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 99. Insulin Receptor PTP: PTP1BINTRODUCTIONPTP1B AS A BONA FIDE IR PHOSPHATASECONCLUSIONREFERENCESChapter 100. STYX/Dead-PhosphatasesINTRODUCTIONGATHERING STYX: STRUCTURE IMPLIES FUNCTIONTHE GRATEFULLY UNDEAD: STYX/DEAD-PHOSPHATASES MEDIATE PHOSPHORYLATION SIGNALINGCONCLUSIONSREFERENCESChapter 101. Zebrafish and Phosphatase FunctionINTRODUCTIONZEBRAFISH AS MODEL SYSTEMZEBRAFISH PROTEIN-TYROSINE PHOSPHATASESFUNCTIONAL ANALYSES OF PTPs IN ZEBRAFISHOUTLOOKREFERENCESChapter 102. Eyes Absent Protein Tyrosine Phosphatases: A New Eukaryotic Branch of the Haloacid Dehalogenase SuperfamilyINTRODUCTIONHAD FAMILY STRUCTURE AND FUNCTIONDISCOVERY OF EUKARYOTIC HAD ENZYMESEYA INTERACTION WITH DEVELOPMENTAL SIGNALS IN DROSOPHILAEYA FUNCTION IN VERTEBRATE DEVELOPMENT AND HUMAN DISEASEEYA PHOSPHATASE FUNCTION AND SUBSTRATE DISCOVERYEXPLORATION OF THE RELATIONSHIP BETWEEN THE DUAL FUNCTIONS OF EYAEYA MAY COORDINATELY REGULATE FATE SPECIFICATION AND TISSUE PATTERNINGACKNOWLEDGEMENTSREFERENCESChapter 103. PHLPP: PH Domain Leucine-Rich Repeat Protein PhosphataseINTRODUCTIONTHE PHLPP FAMILYTARGETS OF PHLPPPHYSIOLOGY AND PATHOPHYSIOLOGY OF PHLPPSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 104. PTENINTRODUCTIONPTEN DISCOVERY AND FUNCTIONPTEN AND CANCERMOUSE MODELS FOR PTEN FUNCTIONPTEN STRUCTURETHE PTEN SIGNALING PATHWAYHAPLOINSUFFICIENCY AND SENESCENCE IN CANCERPTEN IN CANCER THERAPYREFERENCESChapter 105. PTP OxidationINTRODUCTIONPRODUCTION OF ROS AS SECOND MESSENGERSMOLECULAR BASIS FOR PTP OXIDATIONMETHODS FOR DETECTING PTP OXIDATIONOXIDATION OF PTPs IN REGULATING SIGNAL TRANSDUCTIONS-NITROSYLATION OF PTPsCLOSING REMARKS: INVOLVEMENT OF PTP OXIDATION IN HUMAN DISEASESREFERENCESChapter 106. Chronophin and Slingshot Cofilin Phosphatases in Cytoskeletal RegulationINTRODUCTIONREGULATION OF COFILIN ACTIVITYTHE COFILIN PHOSPHATASES: SLINGSHOT SSH)THE COFILIN PHOSPHATASES: CHRONOPHIN CIN)CONCLUSIONS AND FUTURE PROSPECTSACKNOWLEDGEMENTSREFERENCESChapter 107. Large Scale Structural Analysis of Protein Tyrosine PhosphatasesOVERVIEWSTRUCTURAL COVERAGE OF THE FAMILYSTRUCTURAL FEATURESA SHARED CATALYTIC MECHANISMRECEPTOR DIMERIZATIONENDNOTEREFERENCESChapter 108. Protein Phosphatases and Circadian ClocksINTRODUCTION TO CIRCADIAN RHYTHMSREGULATION OF THE CIRCADIAN CLOCK BY PHOSPHORYLATIONPROTEIN PHOSPHATASES AND THEIR CIRCADIAN FUNCTIONWHY IS STUDY OF THE CIRCADIAN FUNCTION OF PHOSPHATASES IMPORTANT?REFERENCESSection C – Calcium Signal TransductionChapter 109. Calcium Signalling; Messengers, Transport Pathways, Sensors, and Physiological OutcomesINTRODUCTIONMECHANISMS, MESSENGERS AND PATHWAYS LEADING TO CALCIUM SIGNALSCALCIUM SENSORS AND HOMEOSTATIC SYSTEMS FOR RECOVERY OF CALCIUM SIGNALSSPECIFIC EXAMPLES OF CALCIUM SIGNALLING IN THE REGULATION OF SMOOTH MUSCLE, CARDIAC MUSCLE AND MITOCHONDRIAL ACTIVITYChapter 110. Phospholipase CINTRODUCTIONPLC ANATOMYPLC ACTIVATION MECHANISMSPLC PHYSIOLOGYREFERENCESChapter 111. Cyclic ADP-ribose and NAADPDISCOVERY OF CADPR AND NAADP AS Ca[sup2+)] MOBILIZING AGENTSMECHANISMS OF Ca[sup2+)] MOBILIZATION BY CADPR AND NAADPSYNTHESIS OF CADPR AND NAADPROLES OF CADPR AND NAADP IN Ca[sup2+)] SIGNALINGCONCLUSIONSREFERENCESChapter 112. Voltage-Gated Calcium ChannelsPHYSIOLOGICAL ROLES OF VOLTAGE-GATED Ca[sup2+)] CHANNELS\Ca[sup2+)] CURRENT TYPES DEFINED BY PHYSIOLOGICAL AND PHARMACOLOGICAL PROPERTIESMOLECULAR PROPERTIES OF Ca[sup2+)] CHANNELSCa[sup2+)] CHANNEL SIGNALING COMPLEXESTHE EFFECTOR CHECKPOINT MODEL OF Ca[sup2+)] CHANNEL REGULATIONREFERENCESChapter 113. Store-Operated Calcium ChannelsSTORE-OPERATED OR CAPACITATIVE CALCIUM ENTRYSTORE-OPERATED CHANNELS – TRPs?MAJOR PLAYERS IDENTIFIED: STIM AND ORAI/CRACMSIGNALING TO STORE-OPERATED CHANNELSREFERENCESChapter 114. Arachidonic Acid-Regulated Ca[sup2+)] ChannelINTRODUCTIONIDENTIFICATION AND CHARACTERIZATION OF ARC CHANNELSSPECIFIC ACTIVATION OF ARC CHANNELS BY LOW AGONIST CONCENTRATIONSROLES OF ARC AND STORE-OPERATED CHANNELS IN [Ca[sup2+)]][subI)] SIGNALS–“RECIPROCAL REGULATION”NEW MOLECULAR INSIGHTS INTO ARC CHANNELS AND THEIR REGULATIONCONCLUSIONS AND IMPLICATIONSACKNOWLEDGEMENTSREFERENCESChapter 115. IP[sub3)] ReceptorsINTRODUCTIONDIVERSITY OF IP[sub3)]RSSTRUCTURE OF IP[sub3)]RREGULATION OF IP[sub3)]RS BY IP[sub3)] AND Ca[sup2+)]MODULATION OF IP[sub3)]RPROTEIN INTERACTIONS WITH IP[sub3)]RREFERENCESChapter 116. Ryanodine ReceptorsFUNCTION AND STRUCTUREACTIVATION OF RYANODINE RECEPTOR Ca[sup2+)] RELEASE CHANNELSMOLECULAR BIOLOGY OF RYANODINE RECEPTORSREFERENCESChapter 117. Intracellular Calcium SignalingTHE “CALCIUM SIGNALING TOOLKIT” AND CALCIUM HOMEOSTASISCHANNELS UNDERLYING Ca[sup2+)] INCREASETEMPORAL REGULATION OF Ca[sup2+)] SIGNALSSPATIAL REGULATION OF Ca[sup2+)] SIGNALSREFERENCESChapter 118. Calcium PumpsINTRODUCTIONPLASMA MEMBRANE CALCIUM ATPASE PMCA)SARCO/ENDOPLASMIC RETICULUM CALCIUM ATPASE SERCA)SECRETORY PATHWAY CALCIUM-TRANSPORT ATPASE SPCA)REFERENCESChapter 119. Sodium/Calcium ExchangeINTRODUCTIONTWO FAMILIES OF PM Na[sup+)]/Ca[sup2+)] EXCHANGERSMODES OF OPERATION OF THE Na[sup+)]/Ca[sup2+)] EXCHANGERSREGULATION OF NCXPHARMACOLOGY OF NCXLOCALIZATION OF THE NCXROLES OF Na[sup+)]/Ca[sup2+)] EXCHANGERS IN PHYSIOLOGY AND PATHOPHYSIOLOGYACKNOWLEDGEMENTSREFERENCESChapter 120. CaCa[sup2+)] BuffersINTRODUCTIONRELEVANT PARAMETERS FOR Ca[sup2+)] BUFFERSCa[sup2+)] BUFFERS AS ONE COMPONENT CONTRIBUTING TO INTRACELLULAR Ca[sup2+)] HOMEOSTASISBIOLOGICAL EFFECTS OF Ca[sup2+)] BUFFERSREFERENCESChapter 121. Mitochondria as Organizers of the Cellular CaCa[sup2+)] Signaling NetworkINTRODUCTIONFUNDAMENTALSTHE PLASTICITY OF THE MITOCHONDRIAL Ca[sup2+)] HANDLING MACHINERYMITOCHONDRIAL Ca[sup2+)] HANDLING IN THE CELLULAR CONTEXTCODAACKNOWLEDGEMENTSREFERENCESChapter 122. EF-Hand Proteins and Calcium Sensing: The Neuronal Calcium Sensor ProteinsINTRODUCTIONCLASS A: NEURONAL CALCIUM SENSOR 1 FREQUENIN)CLASS B: NEUROCALCINS, VILIPS, AND HIPPOCALCINCLASS C: RECOVERINSCLASS D: GUANYLATE CYCLASE ACTIVATING PROTEINS GCAPS)CLASS E: KCHIPSFUTURE PERSPECTIVES FOR THE NCS PROTEIN FAMILYREFERENCESChapter 123. Calmodulin-Mediated SignalingREFERENCESChapter 124. The Family of S100 Cell Signaling ProteinsINTRODUCTIONNOMENCLATUREPROTEIN STRUCTURES, METAL BINDING AND INTERACTIONS WITH TARGET PROTEINSBIOLOGICAL FUNCTIONS AND PATHOLOGIESS100 PROTEINS AND RAGE SIGNALINGCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 125. Annexins and Calcium SignalingINTRODUCTIONANNEXINS AS Ca[sup2+)] CHANNELSANNEXINS AS Ca[sup2+)] CHANNEL REGULATORSCONCLUSIONSREFERENCESChapter 126. CalpainSYNOPSISCALPAIN FAMILYMODES OF REGULATIONCALPAIN AS A SIGNALING INTERMEDIATE: POTENTIAL TARGETSFUNCTIONAL ROLESFUTURE CONSIDERATIONSREFERENCESChapter 127. Calcium Signaling in Smooth MuscleINTRODUCTIONTHE ROLE OF CALCIUM SIGNALING IN SMOOTH MUSCLEOVERVIEW OF TYPES OF CALCIUM SIGNALS IN SMOOTH MUSCLECALCIUM ENTRY MECHANISMSCALCIUM EFFLUX MECHANISMSSR AND CALCIUM SIGNALINGMITOCHONDRIAL AND OTHER ORGANELLAR CONTRIBUTION TO CALCIUM SIGNALINGGLOBAL CALCIUM TRANSIENTSLOCAL CALCIUM SIGNALSCALCIUM OSCILLATIONS AND WAVESCAVEOLAE, MICRODOMAINS, AND CALCIUM SIGNALSREFERENCESChapter 128. Calcium Signaling in Cardiac MuscleINTRODUCTIONCALCIUM-INDUCED CALCIUM RELEASEHOW IS SR CALCIUM CONTENT CONTROLLED?WHICH FACTORS CONTROL THE AMPLITUDE OF THE SYSTOLIC CALCIUM TRANSIENT?CALCIUM SIGNALING IN HEART FAILUREREFERENCESSection D – Lipid-Derived Second MessengersChapter 129. Historical Overview: Protein Kinase C, Phorbol Ester and Lipid MediatorsRETROSPECTIVES OF PHOSPHOLIPID RESEARCHPROTEIN KINASE C AND DIACYLGLYCEROLPHORBOL ESTER AND CELL SIGNALINGSTRUCTURAL HETEROGENEITY AND MODE OF ACTIVATIONTRANSLOCATION AND MULTIPLE LIPID MEDIATORSCONCLUSIONREFERENCESChapter 130. Type I Phosphatidylinositol 4-Phosphate 5-Kinases P14P 5-kinases)INTRODUCTIONBASIC PROPERTIESREGULATIONFUNCTIONACKNOWLEDGEMENTSREFERENCESChapter 131. Type II PIP4-kinasesINTRODUCTIONHISTORYSTRUCTURETYPE II PIP4-KINASE ISOFORMSREGULATIONTHE MOLECULAR AND BIOLOGICAL FUNCTIONS OF THE TYPE II PIP4-KINASESREFERENCESChapter 132. Phosphoinositide 3-KinasesINTRODUCTIONTHE ENZYMESTHE PRODUCTSPHOSPHATASESLIPID BINDING DOMAINSEFFECTORS AND RESPONSESGENETICSPHARMACOLOGYSYNOPSISREFERENCESChapter 133. PTEN/MTM Phosphatidylinositol PhosphatasesPTENMYOTUBULARIN: A NOVEL FAMILY OF PHOSPHATIDYLINOSITOL PHOSPHATASESREFERENCESChapter 134. The Src Homology 2 Containing Inositol 5 PhosphatasesINTRODUCTIONSTRUCTURE AND EXPRESSIONTHE PHENOTYPE OF SHIP1 AND SHIP2 KNOCKOUT MICEMECHANISM OF ACTIONBIOLOGICAL ROLES OF SHIP1 AND SHIP2THERAPEUTIC POTENTIAL OF SHIP 1 AND SHIP2ACKNOWLEDGEMENTSABBREVIATIONSREFERENCESChapter 135. Structural Principles of Lipid Second Messenger RecognitionINTRODUCTIONPHOSPHOLIPID SECOND MESSENGER RECOGNITION BY ACTIVE SITES OF ENZYMESPHOSPHOINOSITIDE-BINDING DOMAINSNON-PHOSPHOINOSITIDE LIPID MESSENGER RECOGNITIONFUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 136. Pleckstrin Homology PH) DomainsIDENTIFICATION AND DEFINITION OF PH DOMAINSTHE STRUCTURE OF PH DOMAINSPH DOMAINS AS PHOSPHOINOSITIDE-BINDING MODULESHIGHLY SPECIFIC RECOGNITION OF PHOSPHOINOSITIDES AND INOSITOL PHOSPHATES) BY PH DOMAINSBINDING OF PH DOMAINS TO NON-PHOSPHOINOSITIDE LIGANDSPOSSIBLE ROLES OF NON-PHOSPHOINOSITIDE PH LIGANDSCONCLUSIONSREFERENCESChapter 137. PX DomainsHISTORY AND OVERVIEW OF PX DOMAINSLIPID-BINDING SPECIFICITY AND STRUCTURE OF PX DOMAINSPHYSIOLOGICAL FUNCTION OF PX DOMAINSREFERENCESChapter 138. FYVE Domains in Membrane Trafficking and Cell SignalingINTRODUCTIONROLE FOR PI3)P IN MEMBRANE TRAFFICKING AND IDENTIFICATION OF THE FYVE DOMAINSTRUCTURAL BASIS FOR PI3)P RECOGNITION BY THE FYVE DOMAINCONSERVATION OF THE FYVE DOMAIN AND LOCALIZATION OF PI3)PFYVE DOMAIN-CONTAINING PROTEINS IN MEMBRANE TRAFFICKINGFYVE DOMAIN-CONTAINING PROTEINS INVOLVED IN PI3)P METABOLISMFYVE DOMAIN-CONTAINING PROTEINS IN SIGNALINGFYVE-LIKE DOMAINSCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 139. Protein Kinase C: Relaying Signals from Lipid Hydrolysis to Protein PhosphorylationABBREVIATIONSINTRODUCTIONPROTEIN KINASE C FAMILYREGULATION OF PROTEIN KINASE CFUNCTION OF PROTEIN KINASE CSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 140. Modulation of Monomeric G Proteins by PhosphoinositidesINTRODUCTIONTHE ARF FAMILY GTPASESTHE RHO FAMILY GTPASESCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 141. Phosphoinositides and Actin Cytoskeletal RearrangementHISTORICAL PERSPECTIVESTIMULATING SITE-SPECIFIC ACTIN POLYMERIZATION IN CELLSTHE MECHANISMS OF ACTIN POLYMERIZATIONPIP5K OVEREXPRESSIONPPI PHOSPHATASE MANIPULATIONSPIP5K RNAI AND GENE KNOCKOUTACTIN-MEMBRANE LINKERS LOCALIZED OR ACTIVATED BY PIP2CONTEXT-DEPENDENT INTERACTION OF PPIS WITH CYTOSKELETAL PROTEINSREFERENCESChapter 142. Phosphatidylinositol Transfer ProteinsINTRODUCTIONSTRUCTURE AND MECHANISM OF LIPID TRANSFER BY PITPPITPα: FUNCTION IN MAMMALIAN CELLSFUNCTION OF PITPβPITP PROTEINS IN C. E LEGANSCONCLUSIONSREFERENCESChapter 143. Inositol Pentakisphosphate: A Signal Transduction HubINTRODUCTIONSYNTHESIS OF INS1,3,4,5,6)P[sub5)]FUNCTIONS OF INS1,3,4,5,6)P[sub5)] AS A PRECURSOR POOLDEPHOSPHORYLATION OF INS1,3,4,5,6)P[sub5)] TO INS3,4,5,6)P[sub4)]PHOSPHORYLATION OF INS1,3,4,5,6)P[sub5)] TO PP-INSP[sub4)]PHOSPHORYLATION OF INS1,3,4,5,6)P[sub5)] TO INSP[sub6)]OTHER FUNCTIONS FOR INS1,3,4,5,6)P[sub5)]: REGULATION OF PTENAN EXPANDING LIST OF FURTHER PROPOSED FUNCTIONS FOR INS1,3,4,5,6)P[sub5)]CONCLUDING STATEMENTREFERENCESChapter 144. Phospholipase DINTRODUCTIONTHE PLD GENE FAMILYVESICLE TRAFFICKINGENDOCYTOSISEXOCYTOSISSIGNAL TRANSDUCTIONPLD, A POTENTIAL DRUG TARGETACKNOWLEDGEMENTSREFERENCESChapter 145. Diacylglycerol KinasesABBREVIATIONSINTRODUCTIONTHE DGK FAMILYREGULATION OF DGKSPARADIGMS OF DGK FUNCTIONCONCLUSIONSREFERENCESChapter 146. Sphingosine-1-Phosphate Receptors: An UpdateINTRODUCTIONTRANSACTIVATION OF S1PRSS1PRS AND THE IMMUNE SYSTEMS1PRS AND THE CARDIOVASCULAR SYSTEMCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 147. Lysophosphatidic Acid and Sphingosine-1-Phosphate Activation of G-Protein-Coupled ReceptorsBRIEF HISTORY AND RECEPTOR NOMENCLATUREVARIABLE CELLULAR RESPONSES VIA LPA AND S1P RECEPTORSRECEPTOR SIGNALING CASCADESMETABOLISM AND ENZYMESKNOCKOUT MICE OVERVIEWACKNOWLEDGEMENTSREFERENCESChapter 148. The Role of Ceramide in Cell RegulationINTRODUCTIONSPHINGOLIPID METABOLISMAPOPTOSISNON-APOPTOTIC CERAMIDE BIOLOGYCONCLUSIONSREFERENCESChapter 149. Role of Phospholipase A2 Forms in Arachidonic Acid Mobilization and Eicosanoid GenerationINTRODUCTIONPLA[sub2)] GROUPSCELLULAR FUNCTION IN AA RELEASECROSS-TALK BETWEEN CPLA[sub2)]α AND SPLA[sub2)]IPLA[sub2)] ROLE IN AA RELEASEREFERENCESChapter 150. Prostaglandin MediatorsINTRODUCTIONTHE CYCLOOXYGENASE PATHWAYPROSTANOID RECEPTORSTHROMBOXANE A[sub2)] TXA[sub2)])PROSTACYCLIN PGI[sub2)])PROSTAGLANDIN D[sub2)] PGD[sub2)])PROSTAGLANDIN E[sub2)] PGE[sub2)])PROSTAGLANDIN F[sub2α)] PGF[sub2α)])CONCLUDING REMARKSREFERENCESChapter 151. Leukotriene MediatorsINTRODUCTION5-LIPOXYGENASEACKNOWLEDGEMENTSREFERENCESChapter 152. Lipoxins and Aspirin-Triggered 15-epi-Lipoxins: Pro-Resolving Mediators in Anti-Inflammation and ResolutionABBREVIATIONSLIPOXIN CHEMICAL SIGNALS IN THE RESOLUTION OF INFLAMMATIONASPIRIN-TRIGGERED LIPOXINS, RESOLVINS, AND PROTECTINSNOVEL ANTI-INFLAMMATORY AND PRO-RESOLVING PATHWAYSCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESSection E – Protein Proximity InteractionsChapter 153. Protein Proximity InteractionsADVANCES IN THE ANALYSIS OF PROTEIN–PROTEIN INTERACTIONSSUBCELLULAR STRUCTURES AND MULTIPROTEIN COMPLEXES THAT CONTRIBUTE TO CELL SIGNALINGKINASE AND PHOSPHATASE TARGETINGChapter 154. Rapid Characterization of in vivo Phosphorylation Sites and the Protein Kinases and Phosphatases that Regulate them by Affinity CaptureINTRODUCTIONANALYSIS OF THE PHOSPHOPROTEOME IN VIVOPHOSPHOPEPTIDE MAPPING USING A COMBINATION OF CRP- AND MS-BASED ANALYSISRAPID PROTEIN KINASE AND PHOSPHATASE IDENTIFICATION BY SMALL MOLECULE AFFINITY CAPTURE AND HIGH THROUGHPUT MASS SPECTROMETRYREFERENCESChapter 155. FRET Analysis of Signaling Events in CellsINTRODUCTIONFLUORESCENT PROBES FOR FRETFRET DETECTION TECHNIQUESCONCLUSIONS AND PROSPECTSREFERENCESChapter 156. The Focal Adhesion: A Network of Molecular InteractionsINTRODUCTIONINTEGRIN ACTIVATIONADHESION STRENGTHENINGINTRACELLULAR SIGNALING AND MOLECULAR SCAFFOLDSFOCAL ADHESION TURNOVERFOCAL ADHESIONS AND GENE EXPRESSIONTHE FUTUREACKNOWLEDGEMENTSREFERENCESChapter 157. WASP and WAVE Family Protein ComplexesINTRODUCTIONWASP AND N-WASP PROTEIN COMPLEXESWAVE/SCAR PROTEIN COMPLEXESCONCLUSIONSREFERENCESChapter 158. Synaptic NMDA-Receptor Signaling ComplexINTRODUCTIONSTRUCTURE OF THE NMDA RECEPTOR SIGNALING COMPLEXORCHESTRATION OF RESPONSES TO Ca[sup2+)] ENTERING THROUGH THE NMDA RECEPTORREFERENCESChapter 159. Toll Family ReceptorsINTRODUCTIONSTRUCTURE–FUNCTION OF TOLL RECEPTORSSIGNALING BY TOLL FAMILY RECEPTORSREFERENCESChapter 160. Signaling and the Immunological SynapseINTRODUCTIONBRIEF INTRODUCTION TO T CELL BIOLOGYINITIATION OF TCR SIGNALINGDEFINITION OF THE IMMUNOLOGICAL SYNAPSEIMMUNOLOGICAL SYNAPSES AND T CELL DEVELOPMENTSYNAPSES AND DIFFERENT KINDS OF T CELLSNATURAL KILLER CELL SYNAPSESTHE FUNCTION OF THE IMMUNOLOGICAL SYNAPSEIMMUNOLOGICAL SYNAPSES AND TCR DOWNREGULATIONCONCLUSIONREFERENCESChapter 161. The Ubiquitin–Proteasome SystemOVERVIEW OF THE UBIQUITIN–PROTEASOME SYSTEMCOMPONENTS OF THE UBIQUITIN LIGATION AND DEUBIQUITYLATION PATHWAYSTHE 20S AND 26S PROTEASOMESDEGRONSEXAMPLES OF REGULATION BY PROTEIN UBIQUITYLATIONACKNOWLEDGEMENTSREFERENCESChapter 162. Caspases: Cell Signaling by ProteolysisPROTEASE SIGNALINGAPOPTOSIS AND LIMITED PROTEOLYSISCASPASE ACTIVATIONREGULATION BY INHIBITORSREFERENCESChapter 163. MAP Kinase in YeastINTRODUCTIONYEAST CELLS USE MULTIPLE MAPKS TO RESPOND TO A WIDE VARIETY OF STIMULIFUNCTIONALLY DEFINING S. CEREVISIAE MAPK CASCADESMAJOR REGULATORY MECHANISMS THAT CONTROL SPECIFICITY IN S. CEREVISAE MAPK CASCADESACKNOWLEDGEMENTSREFERENCESChapter 164. Mammalian MAP KinasesINTRODUCTIONTHE ERK GROUP OF MAP KINASESTHE P38 GROUP OF MAP KINASESTHE JNK GROUP OF MAP KINASESMAP KINASE DOCKING INTERACTIONSSCAFFOLD PROTEINSMORG1POSHOSMSKRP1/MKPX1REFERENCESChapter 165. Subcellular Targeting of PKA through AKAPs: Conserved Anchoring and Unique Targeting DomainsINTRODUCTIONSTRUCTURALLY CONSERVED PKA ANCHORING DETERMINANTSUNIQUE SUBCELLULAR TARGETING DOMAINSPROBING CELLULAR FUNCTIONS OF AKAP–PKA ANCHORINGCONCLUSIONS AND FUTURE DIRECTIONSREFERENCESChapter 166. AKAP Transduction Units: Context dependent Assembly of Signaling ComplexesINTRODUCTIONG-PROTEIN SIGNALING THROUGH AKAP SIGNALING COMPLEXESKINASE/PHOSPHATASE SIGNALING COMPLEXESCAMP SIGNALING UNITSCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 167. Dendritic Protein Phosphatase ComplexesTHE NECESSITY FOR PROTEIN PHOSPHATASE TARGETING IN DENDRITESPHYSIOLOGICAL ROLES OF DENDRITIC PHOSPHATASE SUBSTRATESSUMMARY AND DISCUSSIONACKNOWLEDGEMENTSREFERENCESChapter 168. Protein Phosphatase 2AINTRODUCTIONPP2A REGULATORY SUBUNITS MEDIATE PROXIMITY INTERACTIONSPP2A-INTERACTING PROTEINSREFERENCESChapter 169. 14-3-3 ProteinsINTRODUCTIONSTRUCTURE OF 14-3-3 PROTEINS AND BINDING TO PHOSPHOPROTEINSIDENTIFIED SIGNALING PARTNERS OF 14-3-3 PROTEINS14-3-3σ: CELL CYCLE CONTROL AND TUMOR SUPPRESSION14-3-3 PROTEINS IN PLANT CELL SIGNALINGCONCLUSIONREFERENCESChapter 170. Protein Interaction Data ResourcesOVERVIEWREPRESENTATION OF INTERACTION DATAPROTEIN INTERACTION DATABASESCONCLUSIONSACKNOWLEDGEMENTSREFERENCESSection F – Cyclic NucleotidesChapter 171. Adenylyl CyclasesINTRODUCTIONCLASSIFICATION/STRUCTURE/FUNCTIONENDOGENOUS AND EXOGENOUS REGULATIONROLES IN PHYSIOLOGY AND DISEASESSUMMARYREFERENCESChapter 172. Guanylyl CyclasesHISTORICAL PERSPECTIVEOVERVIEW OF MAMMALIAN GUANYLYL CYCLASESSOLUBLE GUANYLYL CYCLASE, NITRIC OXIDE, AND NITRIC OXIDE SYNTHASEGC-A/NPR-A/NPR1GC-B/NPR-B/NPR2NPR-C/NPR-3GC-C/STARGC-DGC-E/RET-GC1 AND GC-F/RET-GC2GC-GACKNOWLEDGEMENTSREFERENCESChapter 173. Phosphodiesterase FamiliesINTRODUCTIONTHE GENE FAMILIESIMPLICATIONS OF MULTIPLE GENE FAMILIES/SPLICE VARIANTSALTERED PDE EXPRESSION IN PATHOLOGICAL STATESPDE INHIBITORS AS THERAPEUTIC AGENTSWHERE DO WE GO FROM HERE?ACKNOWLEDGEMENTSREFERENCESChapter 174. The cAMP-Specific Phosphodiesterases: A Class of Diverse Enzymes that Define the Properties and Localization of cAMP SignalsINTRODUCTIONSTRUCTURE OF THE cAMP-PDEs: CATALYTIC AND REGULATORY DOMAINSSUBCELLULAR TARGETING OF THE cAMP-PDEs AND CAMP SIGNAL COMPARTMENTALIZATIONREGULATION OF cAMP-PDEsSUMMARYREFERENCESChapter 175. cAMP/cGMP Dual-Specificity PhosphodiesterasesINTRODUCTIONPDE1 Ca[sup2+)]/CALMODULIN-DEPENDENT PDE)PDE2 cGMP-STIMULATED PDE)PDE3 cGMP-INHIBITED CAMP PDE)PDE10PDE11CONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 176. Phosphodiesterase-5INTRODUCTIONGENE ORGANIZATION AND REGULATION OF EXPRESSIONGENERAL STRUCTUREPDE5 CATALYTIC DOMAINPDE5 REGULATORY DOMAINCONCLUDING REMARKSREFERENCESChapter 177. Function and Regulation of Photoreceptor Phosphodiesterase PDE6) in the Visual Signaling PathwayVISUAL TRANSDUCTION PATHWAY IN VERTEBRATE PHOTORECEPTORSTHE CYCLIC NUCLEOTIDE PHOSPHODIESTERASE PDE) SUPERFAMILYOVERALL STRUCTURE OF ROD PDE6 HOLOENZYMECATALYTIC DOMAIN OF PDE6GAF DOMAINS OF PDE6REGULATION OF ROD PDE6 CATALYSIS BY THE γ SUBUNITTRANSDUCIN ACTIVATION MECHANISM OF PDE6PDE6 INTERACTING PROTEINSFUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 178. Regulation of Cyclic Nucleotide Levels by SequestrationINTRODUCTIONSEQUESTRATION OF cGMP IN ROD PHOTORECEPTOR CELLS BY PDE6SEQUESTRATION OF cGMP BY PDE5REFERENCESChapter 179. cAMP-Dependent Protein KinaseINTRODUCTIONCATALYTIC SUBUNITSTRUCTURE OF THE CATALYTIC SUBUNITPROTEIN KINASE INHIBITORREGULATORY SUBUNITSHOLOENZYME COMPLEXESACKNOWLEDGEMENTSREFERENCESChapter 180. Cyclic GMP-Dependent Protein Kinase: Targeting and Control of ExpressionINTRODUCTIONCYCLIC GMP-DEPENDENT PROTEIN KINASE: STRUCTURE AND FUNCTIONTARGETING OF PKG-I IN VSMCROLE OF PKG-I IN THE REGULATION OF VSMC PROLIFERATION AND PHENOTYPEREGULATION OF PKG-I EXPRESSIONREGULATION OF PKG-I MRNA LEVELSFINAL THOUGHTSREFERENCESChapter 181. Inhibitors of Cyclic AMP- and Cyclic GMP-Dependent Protein KinasesINTRODUCTIONCYCLIC NUCLEOTIDE BINDING SITE-TARGETED INHIBITORSATP BINDING SITE-TARGETED INHIBITORSPEPTIDE BINDING SITE-TARGETED INHIBITORSCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 182. Substrates of Cyclic Nucleotide-Dependent Protein KinasesINTRODUCTIONCLASSIFICATION AND NOMENCLATURESUBSTRATES OF PKA AND PKGSTRUCTURAL AND SEQUENCE FEATURES RELEVANT TO PEPTIDE SPECIFICITYCONCLUSIONSREFERENCESChapter 183. Physiological Substrates of PKA and PKGINTRODUCTIONABUNDANCE OF PKA AND PKG PHOSPHORYLATION SITES IN THE HUMAN PROTEOMEPHYSIOLOGICAL SUBSTRATESCONCLUDING REMARKSREFERENCESChapter 184. Effects of cGMP-Dependent Protein Kinase KnockoutsCYCLIC GMP-DEPENDENT PROTEIN KINASES: GENES AND KNOCKOUTSOUTLOOKACKNOWLEDGEMENTREFERENCESChapter 185. Cyclic Nucleotide-Regulated Cation ChannelsINTRODUCTIONGENERAL FEATURES OF CYCLIC NUCLEOTIDE-REGULATED CATION CHANNELSCNG CHANNELSHCN CHANNELSACKNOWLEDGEMENTREFERENCESChapter 186. Epac, cAMP-Regulated Guanine Nucleotide Exchange Factors for Rap1 and Rap2INTRODUCTIONTHE EPAC FAMILYEPAC IS CONSERVED THROUGH EVOLUTIONCOMMON AND SPECIFIC FEATURES OF THE CNB DOMAINSTRUCTURAL BASIS OF ACTIVATIONEXPRESSION AND SUBCELLULAR LOCALIZATION OF EPACCELLULAR FUNCTION OF EPACREFERENCESChapter 187. Cyclic Nucleotide-Binding GAF Domains in Phosphodiesterases and Adenylyl CyclasesINTRODUCTIONCYCLIC NUCLEOTIDE BINDING AND ATOMIC STRUCTURECONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 188. Use of Chimeric Adenylyl Cyclases to Study Cyclic Nucleotide SignalingINTRODUCTIONFUNCTIONAL COMPATIBILITY OF MAMMALIAN AND CYANOBACTERIAL TANDEM GAF DOMAINSCYAB1-PDE2 CHIMERAS TO EXPLORE THE DETERMINANTS OF LIGAND SPECIFICITY IN GAF DOMAINSCYAB1-PDE5 CHIMERAS PROVIDE NEW INSIGHTS INTO TANDEM GAF DOMAINS AS POTENTIAL DRUG TARGETSIDENTIFICATION OF GAF-LIGANDS FOR PDE10 AND PDE11 USING CYAB1 AC CHIMERASCONCLUSIONACKNOWLEDGEMENTREFERENCESChapter 189. Cyclic Nucleotide Signaling in the KinetoplastidsINTRODUCTIONCAMP SIGNALINGADENYLYL CYCLASESCYCLIC NUCLEOTIDE-SPECIFIC PHOSPHODIESTERASESPDEAPDEBPDECPDEDDOWNSTREAM EFFECTORSCGMP SIGNALINGCONCLUSIONSREFERENCESChapter 190. Cyclic Nucleotide Specificity and Cross-Activation of Cyclic Nucleotide ReceptorsMOLECULAR BASIS FOR CAMP/CGMP SELECTIVITY OF PKA AND PKGCONFOUNDING FACTORS IN CROSS-ACTIVATION STUDIESCAMP CROSS-ACTIVATION OF PKGCGMP CROSS-ACTIVATION OF PKAREFERENCESChapter 191. Cyclic Nucleotide Analogs as Tools to Investigate Cyclic Nucleotide SignalingINTRODUCTIONCHEMISTRY AND BASIC PROPERTIES OF CYCLIC NUCLEOTIDE ANALOGSUSE OF CYCLIC NUCLEOTIDE ANALOGS IN CELL BIOLOGY: GUIDELINES AND EXAMPLESBIOAVAILABILITYSIDE EFFECTS AND TOXICITYFUTURE DEVELOPMENTSACKNOWLEDGEMENTSREFERENCESChapter 192. cGMP and PKG Signaling in PlateletsINTRODUCTIONREGULATION OF CGMP SYNTHESIS AND DEGRADATION IN HUMAN PLATELETSPKG SUBSTRATES AND MECHANISMS OF SGC/CGMP/PKG ACTION IN PLATELETSREFERENCESChapter 193. Use of siRNA and Antisense Knockdown to Study Regulation of PKA by PKIINTRODUCTIONKNOCKDOWN OF PKIKNOCKDOWN OF PKIi INCREASES PKA SIGNALINGINHIBITION OF NUCLEAR PKA SIGNALING BY PKI DOES NOT REQUIRE NUCLEAR EXPORTFUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 194. Cyclic Nucleotide Signaling in the Central Nervous SystemABBREVIATIONSCYCLIC NUCLEOTIDE LOCALIZATION IN THE CNSCYCLIC NUCLEOTIDE SIGNALING IN LEARNING AND MEMORY MECHANISMSREGULATION OF ION CHANNELS BY CYCLIC NUCLEOTIDESCYCLIC NUCLEOTIDE SIGNALING IN CIRCADIAN RHYTHMSOTHER cGMP ROLES IN THE CNSREFERENCESChapter 195. Compartmentation of cAMP in cardiomyocytesINTRODUCTIONCELL ARCHITECTURERECEPTOR COUPLING TO G[subi)]RECEPTOR COUPLING TO DIFFERENT ADENYLYL CYCLASE ISOFORMSRESTRICTION OF CAMP DIFFUSIONROLE OF PHOSPHODIESTERASES IN CARDIAC CAMP COMPARTMENTATIONACKNOWLEDGEMENTSREFERENCESChapter 196. Phosphodiesterase-9A: A cGMP-Specific EnzymeINTRODUCTIONPRIMARY STRUCTURE OF PDE9AENZYMATIC PROFILE, INHIBITOR SENSITIVITY, CRYSTAL STRUCTURE, AND SUBCELLULAR LOCALIZATION OF RECOMBINANT PDE9ATISSUE-EXPRESSION PATTERNSPHYSIOLOGICAL ROLES OF PDE9AREFERENCESSection G – G ProteinsChapter 197. Signal Transduction by G Proteins: Basic Principles, Molecular Diversity, and Structural Basis of Their ActionsINTRODUCTIONRAS, THE PROTOTYPIC REGULATORY GTPASEHETEROTRIMERIC G PROTEINSMECHANISM OF G-PROTEIN ACTIVATION BY RECEPTORSMODULATION OF ACTIVITY BY SHORTENING OR EXTENSION OF THE ACTIVE STATEFUTURE DIRECTIONIN MEMORIAMACKNOWLEDGEMENTSREFERENCESChapter 198. Heterotrimeric G-Protein Signaling at Atomic ResolutionINTRODUCTIONARCHITECTURE AND SWITCHING MECHANISM OF THE Gα SUBUNITSINSIGHT INTO THE GTP HYDROLYTIC MECHANISM FROM AN UNEXPECTED TRANSITION STATE MIMICGβγ WITH AND WITHOUT GαPHOSDUCIN AND GGβγG[sub5)]α AND ADENYLYL CYCLASEFILLING IN THE GAPVISUAL FIDELITYWHAT STRUCTURES MAY FOLLOWREFERENCESChapter 199. Functions of Heterotrimeric G ProteinsINTRODUCTIONDEVELOPMENTCENTRAL NERVOUS SYSTEMIMMUNE SYSTEMHEARTSENSORY SYSTEMSHEMOSTASISCONCLUSIONSREFERENCESChapter 200. Regulation of G Proteins by Covalent ModificationINTRODUCTIONN-TERMINAL ACYLATION OF Gα SUBUNITSC-TERMINAL MODIFICATION OF GγSTRUCTURAL AND FUNCTIONAL CONSEQUENCES OF LIPID MODIFICATIONSLIPIDATION INFLUENCES G-PROTEIN TRAFFICKING AND LOCALIZATIONCONCLUSIONSREFERENCESChapter 201. G-Protein-Coupled Receptors, Signal Fidelity, and Cell TransformationINTRODUCTIONGPCRS AND ONCOGENESISA MAPK SIGNALING NETWORK LINKS GPCRS TO BIOLOGICAL OUTCOMESERK CASCADEG PROTEIN-INDEPENDENT SIGNALINGGPCR EFFECTORS ARE ORGANIZED BY SCAFFOLDING MOLECULESCONCLUSION: GPCR BIOLOGY REQUIRES BOTH SIGNAL INTEGRATION AND FIDELITYACKNOWLEDGEMENTSREFERENCESChapter 202. Signaling Through G[subz)]INTRODUCTIONGENERAL PROPERTIESREGULATORS OF G[subZ) SIGNALING: RGS PROTEINSRECEPTORS THAT COUPLE TO G[subZ)]EFFECTORS OF G[subZ)] SIGNALINGPHENOTYPE OF Gα[subZ)] KNOCKOUT MICECONCLUDING REMARKSREFERENCESChapter 203. Effectors of Gα[subo)]INTRODUCTIONG[subI/O) SIGNALINGINDUCTION OF NEURITE OUTGROWTH BY GG[subI/O)SIGNALING TO THE NUCLEUSSIGNALING TO THE CYTOSKELETONG[subI/O) SIGNALING AND NEUROPROTECTIONACKNOWLEDGEMENTSREFERENCESChapter 204. Mono-ADP-Ribosylation of Heterotrimeric G ProteinsINTRODUCTIONTHE MONO-ADP-RIBOSYLATION REACTIONBACTERIAL-TOXIN-INDUCED ADP-RIBOSYLATIONENDOGENOUS MONO-ADP-RIBOSYLATIONACKNOWLEDGEMENTSREFERENCESChapter 205. Specificity of G-Protein βγ Dimer SignalingINTRODUCTIONDIVERSITY OF γAPPLICATION OF GENETIC SYSTEMS FOR ANALYSIS OF γ SPECIFICITYCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 206. The Superfamily of Regulator of G-Protein Signaling RGS) ProteinsINTRODUCTIONTHE SIGNATURE RGS DOMAIN AS A GAP FOR Gα GTPGα GAP AND OTHER SIGNALING REGULATORY ACTIVITIES OF RGS FAMILY MEMBERSACKNOWLEDGEMENTSREFERENCESChapter 207. G-Protein Signaling in ChemotaxisINTRODUCTIONCHEMOTAXIS: MEMBRANE EXTENSIONS, DIRECTIONAL SENSING, AND POLARIZATIONCHEMOATTRACTANT SIGNALING REGULATES MULTIPLE DOWNSTREAM PATHWAYSFRONT AND BACK SIGNALINGMECHANISMS OF DIRECTIONAL SENSINGPOLARIZATIONCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 208. Reversible Palmitoylation in G Protein SignalingINTRODUCTIONSITES OF PALMITOYLATION IN Gα AND RGS PROTEINSACTIVATION-REGULATED PALMITOYLATION OF GαMECHANISMS OF REVERSIBLE PALMITOYLATIONFUNCTIONS OF REVERSIBLE PALMITOYLATIONCONCLUSIONREFERENCESChapter 209. G Proteins in Gustatory TransductionINTRODUCTIONα-GUSTDUCINα-TRANSDUCINOTHER G-PROTEIN α SUBUNITSβγ SUBUNITSG-PROTEIN-COUPLED RECEPTORSSECOND-MESSENGER PATHWAYSTASTE RECEPTORS AND G PROTEINS IN GASTROINTESTINAL TRACTCONCLUSIONSREFERENCEChapter 210. Regulation of Synaptic Fusion by Heterotrimeric G ProteinsINTRODUCTIONTHE VESICLE FUSION MACHINERYMODES OF SYNAPTIC VESICLE FUSIONG-PROTEIN-COUPLED RECEPTOR MEDIATED MODULATION AT THE PRESYNAPTIC TERMINALPOSSIBLE MECHANISMS OF PRESYNAPTIC INHIBITION BY G PROTEINSGα[subQ)] SIGNALING Ca[sup2+)] STORES, DAG AND MODULATION OF NEUROTRANSMITTER RELEASEG PROTEINS AND PHOSPHORYLATIONREFERENCESChapter 211. G-Protein Regulation of ChannelsINTERACTION WITH K[sup+)] CHANNELSCALCIUM CHANNEL INTERACTION WITH G PROTEINSREFERENCESChapter 212. Ras and CancerINTRODUCTION: RAS ACTIVATION IN CANCERPATHWAYS DOWNSTREAM OF RASMOUSE MODELS OF CANCERPROSPECTS FOR CANCER THERAPY BASED ON RASREFERENCESChapter 213. The Influence of Intracellular Location on Function of Ras ProteinsINTRODUCTIONDOES LOCATION ACTUALLY INFLUENCE RAS SIGNALING?MODIFICATIONS BY ENDOMEMBRANE ENZYMES – NEW OPPORTUNITIES TO ABORT RAS TRAFFICKING?RAS PROTEINS BEGIN THEIR MARCH TOWARD THE CELL SURFACERAS ACTIVATION ON ER AND GOLGI MEMBRANESDESTINATION CELL SURFACE: RAS PROTEINS DISTRIBUTE AMONG SEVERAL PLASMA MEMBRANE DOMAINSNEW DESTINATIONS – MITOCHONDRIAOLD DESTINATIONS – ENDOSOMESA REALITY CHECK – THE FIRST STRUCTURES OF LIPID-MODIFIED RAS ON LIPID MEMBRANESREFERENCESChapter 214. Role of R-Ras in Cell GrowthINTRODUCTIONGENERAL PROPERTIES OF R-RAS PROTEINS: VARIATIONS ON RASR-RASTC21/R-RAS-2M-RAS/R-RAS-3CONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 215. The Ran GTPase: Cellular Roles and RegulationINTRODUCTIONSTRUCTURAL ANALYSIS OF RAN PATHWAY COMPONENTSRAN’S ROLE IN NUCLEAR TRANSPORTRAN’S FUNCTION IN SPINDLE ASSEMBLYRAN’S FUNCTION IN CELL CYCLE PROGRESSIONRAN’S ROLE IN NUCLEAR ENVELOPE DYNAMICSBIOLOGICAL REGULATION OF CORE RAN PATHWAY COMPONENTSCONCLUSIONSREFERENCESChapter 216. Regulation of NADPH Oxidases by Rac GTPaseINTRODUCTIONPROTEIN COMPONENTS AND REGULATION OF THE PHAGOCYTE NADPH OXIDASEREGULATION OF RAC ACTIVITYTHE ROLE OF RAC IN NADPH OXIDASE REGULATIONCURRENT MODELS OF RAC FUNCTION IN NADPH OXIDASE REGULATIONRAC GTPASE – A MORE GENERAL ROLE IN REGULATING OXIDANT-BASED SIGNALING?REFERENCESChapter 217. The Role of Rac and Rho in Cell Cycle ProgressionINTRODUCTIONREGULATION OF G1 PROGRESSIONTHE FUNCTION OF RAC AND RHO IN CELL CYCLE PROGRESSION AND TRANSFORMATIONCELL CYCLE TARGETS OF RAC AND RHOFUTURE PERSPECTIVESACKNOWLEDGEMENTREFERENCESChapter 218. Cdc42 and Its Cellular FunctionsINTRODUCTIONCDC42 REGULATES A VARIETY OF CELLULAR FUNCTIONSSPATIAL AND TEMPORAL CONTROL OF CDC42 ACTIVITYCOOPERATION BETWEEN CDC42 AND OTHER SMALL GTPASES IN CELLULAR FUNCTIONSCONCLUSIONREFERENCESChapter 219. Tissue Transglutaminase: A Unique GTP-binding/GTPaseGENERAL STRUCTURAL CONSIDERATIONS REGARDING THE GTP-BINDING AND GTP-HYDROLYTIC ACTIVITY OF TGASE-2WHAT IS IMPORTANT FOR GTP-BINDING ACTIVITY?WHAT IS IMPORTANT FOR GTP-HYDROLYTIC ACTIVITY?HOW DO GUANINE NUCLEOTIDES IMPACT TRANSAMIDATION ACTIVITY?WHAT IS IMPORTANT FOR Ca[sup2+)] REGULATION OF TGASE-2?BIOLOGICAL IMPLICATIONS FOR THE GTP-BINDING ACTIVITY OF TGASE-2BIOLOGICAL IMPLICATIONS OF THE ENZYMATIC TRANSAMIDATION ACTIVITY OF TGASE-2FUTURE DIRECTIONS AND CONCLUDING REMARKSREFERENCESChapter 220. Roles for ADP-Ribosylation Factors in Membrane TrafficTHE ARF FAMILY OF REGULATORY GTPASESARFS AS REGULATORS OF LIPID-MODIFYING ENZYMESARF AS INITIATOR OF CARRIER COATING VIA ADAPTOR RECRUITMENTCOPISUMMARY AND FUTURE DIRECTIONSNOTESREFERENCESChapter 221. Yeast Small G Protein Function: Molecular Basis of Cell Polarity in YeastINTRODUCTIONTHE RSR1/BUD1 RAS-LIKE GTPASE MODULE INTERPRETS SPATIAL LANDMARKSTHE CDC42 RHO-LIKE GTPASE MODULE REGULATES THE ESTABLISHMENT OF CELL POLARITYCOUPLING THE RSR1 GTPASE MODULE TO THE CDC42 GTPASE MODULEREGULATION OF CDC42 POLARIZATIONTHE CDC42 GTPASE MODULE EFFECTS ACTIN ASSEMBLY AND SECRETION AT SITES OF POLARIZED GROWTHCONCLUDING REMARKSREFERENCESChapter 222. Farnesyltransferase InhibitorsINTRODUCTIONFARNESYLATION AND PROTEIN FUNCTIONRAS – THE PROTOTYPE OF FARNESYLATED PROTEINSIDENTIFICATION AND DEVELOPMENT OF FTISFTI ACTIVITY IN CELL CULTURE AND ANIMAL MODELSALTERNATIVE PRENYLATION IN THE PRESENCE OF FTIsFTIs AS PHARMACOLOGICAL TOOLS TO STUDY SIGNALING AND BIOLOGYTARGETS OF FTIsINHIBITION OF SIGNALING BY FTIsSUMMARY AND PROSPECTSREFERENCESChapter 223. Structure of Rho Family TargetsRHO SUBFAMILY PROTEIN STRUCTURES AND CONFORMATIONAL SWITCHCRIB PROTEINSNON-CRIB RAC EFFECTORSRHO EFFECTORSROCKCONCLUDING REMARKSREFERENCESChapter 224. Structural Features of RhoGEFsINTRODUCTIONSTRUCTURAL ACCOMPLISHMENTSDH DOMAIN FEATURESDH-ASSOCIATED PH DOMAINSPH DOMAIN CONFIGURATIONSMECHANISM OF NUCLEOTIDE EXCHANGEMOLECULAR RECOGNITION OF RHO GTPASE SUBSTRATESEXTERNAL REGULATION OF THE DH AND PH DOMAINSREFERENCESChapter 225. Structural Considerations of Small GTP-Binding ProteinsINTRODUCTIONTHE G-DOMAIN FUNCTIONAL UNITTHE CONFORMATIONAL SWITCHGUANINE NUCLEOTIDE EXCHANGE FACTORSEFFECTOR BINDING VIA SWITCHES AND OTHERSGAP PROTEINS AND THE GTPASE REACTIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 226. Mx Proteins: High Molecular Weight GTPases with Antiviral ActivityINTRODUCTIONMX PROTEINS BELONG TO THE SUPERFAMILY OF HIGH MOLECULAR WEIGHT GTPASESINDUCTION OF MX GENE EXPRESSION BY INTERFERONSSUBCELLULAR LOCALIZATION OF MX PROTEINSANTIVIRAL PROPERTIES OF MX PROTEINSMX OLIGOMERIZATION AND ACCESSORY FACTORSACKNOWLEGEMENTSREFERENCESSection H – Developmental SignalingChapter 227. Interactions between Wnt/β-Catenin/Fgf and Chemokine Signaling in Lateral Line MorphogenesisINTRODUCTIONFGF SIGNALING CONTROLS SENSORY ORGAN FORMATION IN THE MIGRATING PRIMORDIUMWNT/β-CATENIN SIGNALING RESTRICTS NEUROGENESIS TO TRAILING CELLS AND MAINTAINS THE PROGENITOR ZONETHE FGF PATHWAY RESTRICTS WNT/β-CATENIN SIGNALING TO THE LEADING EDGE ENSURING NORMAL MIGRATIONCHEMOKINE SIGNALING GUIDES THE MIGRATING PRIMORDIUMA FEEDBACK LOOP BETWEEN FGF AND WNT/β-CATENIN SIGNALING CONTROLS MIGRATION BY LOCALIZING CHEMOKINE RECEPTOR EXPRESSIONCELL MIGRATION AND ROSETTOGENESIS ARE INDEPENDENTLY REGULATEDSUMMARYREFERENCESChapter 228. Wnt Signaling in DevelopmentINTRODUCTIONCANONICAL WNT SIGNALINGWNT SIGNALING IN INVERTEBRATE DEVELOPMENTWNT SIGNALING IN VERTEBRATE DEVELOPMENTWNT/PLANAR CELL POLARITYACKNOWLEDGEMENTSREFERENCESChapter 229. Hedgehog Signaling in Development and DiseaseTHE HEDGEHOG PROTEINS: GENERATION AND DISTRIBUTIONTRANSMITTING THE HH SIGNALHH IN DEVELOPMENT AND DISEASEACKNOWLEDGEMENTSREFERENCESChapter 230. Regulation of Vertebrate Left-Right Axis Development by CalciumINTRODUCTIONCONSERVED MOLECULAR PATHWAYS REGULATING LR ASYMMETRYINITIATING A BREAK IN SYMMETRYCONSERVED ROLE OF CALCIUM IN LEFT–RIGHT ASYMMETRY DETERMINATIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 231. LIN-12/Notch Signaling: Induction, Lateral Specification, and Interaction with the EGF/Ras PathwayTHE LIN-12/NOTCH PATHWAYINDUCTIVE SIGNALING VERSUS LATERAL SPECIFICATIONCELLULAR OUTCOME OF THE ACTIVATION OF THE LIN-12/NOTCH PATHWAYACKNOWLEDGEMENTREFERENCESChapter 232. Proteolytic Activation of Notch Signaling: Roles for Ligand Endocytosis and MechanotransductionINTRODUCTIONDSL LIGAND ENDOCYTOSIS IS REQUIRED FOR ACTIVATION OF NOTCH SIGNALINGNOTCH SIGNALING REQUIRES PROTEOLYSIS AND NUCLEAR TRANSLOCATIONDSL LIGAND ENDOCYTOSIS TO PRODUCE A FORCE FOR NOTCH PROTEOLYTIC ACTIVATIONUBIQUITIN AND EPSIN-DEPENDENT RECYCLING TO PRODUCE AN ACTIVE DSL LIGANDCONVERTING DSL LIGAND ENDOCYTOSIS INTO A FORCE-GENERATING PROCESSCONCLUSIONS AND FUTURE DIRECTIONSREFERENCESChapter 233. BMPs in DevelopmentINTRODUCTIONBMP SIGNAL TRANSDUCTIONEXTRACELLULAR AND INTRACELLULAR BMP ANTAGONISTS AND THE ESTABLISHMENT OF MORPHOGEN GRADIENTSBMPS IN VERTEBRATE EMBRYO PATTERNINGBMPS AND BONE DEVELOPMENTPERSPECTIVESREFERENCESChapter 234. Neurotrophin Signaling in DevelopmentINTRODUCTIONTHE NEUROTROPHIN LIGANDSNEUROTROPHIN RECEPTORSSIGNALING SPECIFICITY DURING DEVELOPMENTINTERACTING PROTEINSRETROGRADE AXONAL TRANSPORTNEUROTROPHIN SIGNALING IN THE ADULT NERVOUS SYSTEMREFERENCESChapter 235. Mechanisms Underlying Context-Dependent VEGF Signaling For Distinct Biological ResponsesINTRODUCTIONDIVERSITY OF PROTEINS GENERATED BY THE VEGFA GENEINTERACTION OF VEGF WITH EXTRACELLULAR MATRIX MOLECULESANTI-ANGIOGENIC THERAPY TARGETING VEGFINTRACRINE VEGF SIGNALINGCONCLUSIONSREFERENCESChapter 236. Vascular Endothelial Growth Factors and Receptors: Signaling in Vascular DevelopmentINTRODUCTION TO VEGFs AND VEGF RECEPTORSDEVELOPMENTAL PROCESSES; VASCULOGENESIS AND ANGIOGENESISVEGFR2 AND ITS LIGANDS IN VASCULAR DEVELOPMENTVEGFR1 AND ITS LIGANDS IN VASCULAR DEVELOPMENT AND INFLAMMATORY RESPONSESVEGFR3 AND ITS LIGANDS IN LYMPHATIC DEVELOPMENTVEGF AND ITS CORECEPTORS IN MODULATION OF SIGNAL TRANSDUCTIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 237. Signaling from Fibroblast Growth Factor Receptors in Development and DiseaseINTRODUCTIONFGFR EXPRESSION AND ROLE DURING DEVELOPMENTSIGNALING PATHWAYS MEDIATED BY FGFRSFGFRS AND DEVELOPMENTAL DISORDERSROLE OF FGFRS IN HUMAN CANCERREFERENCESChapter 238. The Role of Receptor Protein Tyrosine Phosphatases in Axonal PathfindingINTRODUCTIONRPTPS AND THE VISUAL SYSTEMNEUROMUSCULAR SYSTEMFURTHER AXON GROWTH AND GUIDANCE ROLESAXONAL SIGNALING BY RPTPSREFERENCESChapter 239. Attractive and Repulsive Signaling in Nerve Growth Cone NavigationINTRODUCTIONNETRIN SIGNALINGSEMAPHORIN SIGNALINGSLIT SIGNALINGEPHRIN SIGNALINGNOGO AND MYELIN-ASSOCIATED GLYCOPROTEIN SIGNALINGCRITICAL ROLES OF MODULATORY SIGNALSCONCLUDING REMARKSREFERENCESChapter 240. Semaphorins and their Receptors in Vertebrates and InvertebratesTHE SEMAPHORIN FAMILYRECEPTORS FOR SEMAPHORINSINTRACELLULAR SIGNALING PATHWAYSCRMPSUMMARY AND FUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 241. Signaling Pathways that Regulate Cell Fate in the Embryonic Spinal CordINTRODUCTIONPATTERNING ALONG THE DORSOVENTRAL AXISDORSAL SPINAL CORD DEVELOPMENTVENTRAL SPINAL CORD DEVELOPMENTROSTROCAUDAL SPECIFICATIONREFERENCESChapter 242. Cadherin Regulation of Adhesive InteractionsINTRODUCTIONTHE CADHERIN FAMILYCADHERIN STRUCTURE–FUNCTION RELATIONSHIPSMULTIPLE MODES FOR REGULATING CADHERIN ADHESIVE ACTIVITYCONCLUSIONS AND PERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 243. Integration of BMP, RTK, and Wnt Signaling through Smad1 PhosphorylationsINTRODUCTIONNEURAL INDUCTION: LINKING RTKS AND ANTI-BMP SIGNALSMAPK ACTIVATION EXPLAINS HETEROLOGOUS NEURAL INDUCERSEPIDERMAL DIFFERENTIATION: INTEGRATION OF WNT AND BMP SIGNALSSMAD1 AS A PLATFORM FOR MAPK INTEGRATIONSMAD1 AS A PLATFORM FOR WNT SIGNALSA CONSERVED MECHANISM OF SIGNAL INTEGRATIONCONCLUDING REMARKSREFERENCESe9780123741455v3Front CoverHandbook of Cell SignalingCopyright PageContentsContributorsPreface to the Second EditionPreface to the First EditionPart III: Transcription and Translation: Nuclear and Cytoplasmic EventsINTRODUCTIONSection A – Nuclear ReceptorsChapter 244. Nuclear Receptor CoactivatorsINTRODUCTIONLIGAND-DEPENDENT INTERACTION BETWEEN NUCLEAR RECEPTORS AND COACTIVATORSPOSTTRANSLATIONAL MODIFICATIONS PERFORMED BY COACTIVATOR COMPLEXESCONCLUSIONSREFERENCESChapter 245. Corepressors in Mediating Repression by Nuclear ReceptorsINTRODUCTIONCOREPRESSORS BOUND TO UNLIGANDED RECEPTORCONTROL OF COREGULATOR EXCHANGETRANSREPRESSION STRATEGIESCOREPRESSORS AS METABOLIC SENSORSDISEASE MECHANISMS OF NUCLEAR RECEPTOR DEPENDENT TRANSREPRESSIONFUTURE DIRECTIONSREFERENCESChapter 246. Steroid Hormone Receptor SignalingINTRODUCTIONACTIVATION BY THE HORMONEHORMONE INDEPENDENT ACTIVATIONCROSS-TALK WITH OTHER TRANSCRIPTION FACTORSNON-GENOMIC ACTION OF STEROID HORMONESTHE ERRSSELECTIVE STEROID HORMONE RECEPTOR MODULATORSACKNOWLEDGEMENTSREFERENCESChapter 247. Role of COUP-TFII in Congenital Diaphragmatic HerniaINTRODUCTIONCLINICAL FEATURES OF CDHBASIC ASPECTS OF COUP-TFSMOUSE LACKING COUP-TFII IS AN ANIMAL MODEL OF BOCHDALEK TYPE CDHCDH AND DELETION OF CHROMOSOME 15Q26COUP-TFII AS A POTENTIAL MASTER REGULATOR OF DIAPHRAGM FORMATIONPERSPECTIVESACKNOWLEDGEMENTSREFERENCESChapter 248. Nuclear Receptors in Drosophila MelanogasterOVERVIEWTHE ECDYSTEROID RECEPTOR AND DROSOPHILA DEVELOPMENTTHE LARVAL SALIVARY GLAND: RECEPTOR MEDIATED REGULATION IN A DEVELOPING ORGANOTHER NUCLEAR RECEPTORS PARTICIPATE IN ECDYSTEROID REGULATIONCELL CULTURE: ANALYSIS OF RECEPTOR CAPABILITIES AND IN VIVO TESTSJUVENILE HORMONE AND NUCLEAR RECEPTOR ACTIVITYNUCLEAR RECEPTOR ROLES IN PATTERN FORMATION, DIFFERENTIATION, AND REPRODUCTIVE PROCESSESMAJOR THEMESACKNOWLEDGEMENTSREFERENCESSection B – Transcription FactorsChapter 249. JAK-STAT SignalingABBREVIATIONSINTRODUCTIONTHE JAK-STAT PARADIGMTHE JAK FAMILYTHE STAT FAMILYA BRIGHT FUTUREREFERENCESChapter 250. FOXO Transcription Factors: Key Targets of the PI3K-Akt Pathway That Regulate Cell Proliferation, Survival, and Organismal AgingINTRODUCTIONIDENTIFICATION OF THE FOXO SUBFAMILY OF TRANSCRIPTION FACTORSREGULATION OF FOXO TRANSCRIPTION FACTORS BY THE PI3K-AKT PATHWAYOTHER REGULATORY PHOSPHORYLATION SITES IN FOXOSMECHANISM OF THE EXCLUSION OF FOXOS FROM THE NUCLEUS IN RESPONSE TO GROWTH FACTOR STIMULATIONTRANSCRIPTIONAL ACTIVATOR PROPERTIES OF FOXOSFOXOS AND THE REGULATION OF APOPTOSISFOXOS ARE KEY REGULATORS OF SEVERAL PHASES OF THE CELL CYCLEFOXOS IN CANCER DEVELOPMENT: POTENTIAL TUMOR SUPPRESSORSROLE OF FOXOS IN THE RESPONSE TO STRESS AND ORGANISMAL AGINGFOXOS AND THE REGULATION OF METABOLISM IN RELATION TO ORGANISMAL AGINGCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 251. The Multi-Gene Family of Transcription Factor AP-1INTRODUCTIONGENERAL STRUCTURE OF THE AP-1 SUBUNITSTRANSCRIPTIONAL AND POSTTRANSLATIONAL CONTROL OF AP-1 ACTIVITYFUNCTION OF MAMMALIAN AP-1 SUBUNITS DURING EMBRYOGENESIS AND TISSUE HOMEOSTASIS: LESSONS FROM LOSS-OF-FUNCTION AND GAIN-OF-FUNCTION APPROACHES IN MICEFUNCTION OF MAMMALIAN AP-1 SUBUNITS DURING CANCER DEVELOPMENT AND PROGRESSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 252. NFκB: A Key Integrator of Cell SignalingREFERENCESChapter 253. Transcriptional Regulation via the cAMP Responsive Activator CREBTHE CREB FAMILY OF TRANSCRIPTION FACTORSDOMAIN STRUCTURE AND FUNCTIONOVERVIEW OF CREB ACTIVATIONKEY PHOSPHORYLATION EVENTSCREB TARGET GENESCBP AND P300TORCOTHER COACTIVATORS AND INTERACTING PROTEINSQUESTIONS TO BE ADDRESSEDACKNOWLEDGEMENTSREFERENCESChapter 254. The NFAT Family: Structure, Regulation, and Biological FunctionsINTRODUCTIONSTRUCTURE AND DNA BINDINGREGULATIONTRANSCRIPTIONAL FUNCTIONSBIOLOGICAL PROGRAMS REGULATED BY NFATTHE PRIMORDIAL FAMILY MEMBER: NFAT5PERSPECTIVESREFERENCESChapter 255. Ubiquitination/ProteasomePROTEIN DEGRADATION AND THE UBIQUITIN/PROTEASOME SYSTEMREGULATION OF UBIQUITINATION BY SUBSTRATE MODIFICATIONREGULATION OF UBIQUITIN LIGASE ACTIVITYPROCESSING OF TFS BY THE UBIQUITIN SYSTEMMODULATION OF KINASE ACTIVITY BY UBIQUITINATIONROLE OF UBIQUITINATION/PROTEASOME IN TF ACTIVITYCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 256. The SmadsHISTORY AND CATEGORIZATION: R-SMADS, CO-SMADS, AND I-SMADSSMAD REGULATION BY RECEPTORS AND NUCLEOCYTOPLASMIC SHUTTLINGTRANSCRIPTIONAL REGULATION BY SMADSDOWNREGULATION AND CROSS-REGULATION OF SMADSFUNCTION OF SMADS IN VIVO: GAIN OF FUNCTION AND LOSS OF FUNCTION EXPERIMENTSACKNOWLEDGEMENTSREFERENCESSection C – Damage/Stress ResponsesChapter 257. Complexity of Stress SignalingABBREVIATIONSINTRODUCTIONORIGIN OF STRESS RESPONSE SIGNALSSIGNAL TRANSDUCTIONSYSTEMS LEVEL DEDUCTIONS OF STRESS RESPONSE NETWORKSACKNOWLEDGEMENTREFERENCESChapter 258. Signal Transduction in the Escherichia coli SOS ResponseINDUCING THE SOS REGULATORY NETWORKCELLULAR CONSEQUENCES OF SOS INDUCTIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 259. Oxidative Stress and Free Radical Signal TransductionINTRODUCTION: REDOX BIOLOGYOXIDATIVE STRESS RESPONSES IN BACTERIA: SOME WELL-DEFINED MODELS OF REDOX SIGNAL TRANSDUCTIONRESPONSE TO SUPEROXIDE STRESS AND NITRIC OXIDE: SOXR PROTEINRESPONSE TO H[sub2)]O[sub2)] AND NITROSOTHIOLS: OXYR PROTEINPARALLELS IN REDOX AND FREE RADICAL SENSINGTHEMES IN REDOX SENSINGACKNOWLEDGEMENTSREFERENCESChapter 260. Screening Approaches to Identify Genes Required for DNA Double-Strand Break Damage Signaling in the Yeast Saccharomyces cerevisiaeINTRODUCTIONSENSING DSB DAMAGE AND ITS BIOLOGICAL CONSEQUENCESNATURE OF DSB MAY DETERMINE REPAIR AND GENETIC CONSEQUENCESCHECKPOINT ACTIVATION AND ADAPTATION ARE SIGNALING RESPONSES TO DSBSEXTENSIVE DNA DAMAGE SIGNALING NETWORKS HAVE BEEN REVEALED THROUGH GENETIC AND GENOME-WIDE SCREENS IN YEASTIDENTIFYING CHECKPOINT DEFECTS BY SCREENING RADIATION SENSITIVE MUTANTSCHECKPOINT MUTANTS CAN BE REVEALED THROUGH SCREENING DNA REPLICATION MUTANTSSCREENING FOR CHECKPOINT DEFECTS ASSOCIATED WITH DAMAGE INDUCED CHANGES IN TRANSCRIPTION ALSO IDENTIFIES KINASE MUTANTSSCREEN FOR ALTERED CHECKPOINT AND ADAPTATION RESPONSES TO A SINGLE DSBSCREENS FOR G1 CHECKPOINT AND CHECKPOINT ADAPTATION MUTANTSOTHER SCREENS FOR DNA DAMAGE CHECKPOINT PATHWAY GENESIMPLICATIONS OF DNA DAMAGE CHECKPOINT SIGNALINGREFERENCESChapter 261. Radiation Responses in DrosophilaINTRODUCTIONSENSORS AND TRANSDUCERSEFFECTORSCONCLUSIONS: WHAT CAN WE LEARN FROM THE DROSOPHILA MODEL?REFERENCESChapter 262. Double-Strand Break Recognition and its Repair by Non-Homologous End-JoiningOVERVIEW OF NON-HOMOLOGOUS END-JOINING NHEJ)KINASE ACTIVATION AND AUTOPHOSPHORYLATION OF DNA-PKDNA-PK MAY INFLUENCE THE BALANCE OF HR AND NHEJ DURING S PHASELOCAL CHROMATIN STRUCTURE AT SITES OF NHEJREFERENCESChapter 263. ATM Mediated Signaling Defends the Integrity of the GenomeINTRODUCTIONSENSING RADIATION DAMAGE IN DNAATM ACTIVATION AND RECRUITMENT OF DNA DAMAGE RESPONSE PROTEINS TO DNA DSBATM MEDIATED DOWNSTREAM SIGNALINGCELL CYCLE CHECKPOINT ACTIVATIONCONCLUDING REMARKSREFERENCESChapter 264. Signaling to the p53 Tumor Suppressor through Pathways Activated by Genotoxic and Non-Genotoxic StressesINTRODUCTIONP53 PROTEIN STRUCTUREPOSTTRANSLATIONAL MODIFICATIONS TO P53REGULATION OF P53 ACTIVITYP53 STABILIZATIONP53 ACTIVATIONACTIVATION OF P53 BY GENOTOXIC STRESSESDNA DOUBLED-STRAND BREAKSREPLICATION STRESS AND SINGLE-STRANDED DNAREPLICATIVE SENESCENCEONCOGENE ACTIVATIONOTHER GENOTOXIC AGENTSACTIVATION OF P53 BY NON-GENOTOXIC STRESSESTHE UNFOLDED PROTEIN RESPONSE – ER STRESSHYPOXIAGLUCOSE DEPRIVATION – NUTRITIONAL STRESSRIBONUCLEOTIDE POOL IMBALANCENUCLEOLAR AND RIBOSOMAL STRESSMICROTUBULE DISRUPTIONSETTING THRESHOLDS AND RESETTING ACTIVATION – P53 PHOSPHATASESCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 265. The p53 Master Regulator and Rules of Engagement with Target SequencesINTRODUCTIONTHE p53 INDUCED TRANSCRIPTIONAL NETWORK: GENES, BIOLOGICAL FUNCTIONS, AND THE COMPLEXITY OF TARGET SELECTIONYEAST AS AN IN VIVO TEST TUBE TO STUDY WILD-TYPE AND MUTANT p53 TRANSACTIVATION POTENTIAL TOWARD DEFINED RESPONSE ELEMENT SEQUENCESA RHEOSTATABLE YEAST PROMOTER FOR CONTROLLED, INDUCIBLE EXPRESSIONRULES OF p53 TRANSACTIVATION REVEALED BY YEAST-BASED ASSAYSSPACERS AFFECT p53 TRANSACTIVATION POTENTIAL IN THE YEAST-BASED ASSAYSPACER EFFECTS ON p53 BINDING AND TRANSACTIVATION IN MAMMALIAN CELL ASSAYSNON-CANONICAL 3/4- AND 1/2-SITE RES EXPAND THE p53 TRANSCRIPTIONAL NETWORKIMPACT OF 1/2-SITE RES IN THE p53 TRANSCRIPTIONAL NETWORKEVOLUTIONARY DEVELOPMENT OF p53 RESYEAST BASED FUNCTIONAL CLASSIFICATION OF p53 MUTANT ALLELES ASSOCIATED WITH CANCERCONTRIBUTIONS TO THE RULES OF ENGAGEMENT BY p53 HOMOLOGS AND OTHER SEQUENCE SPECIFIC TRANSCRIPTION FACTORSp53 COFACTORS CONTRIBUTE TO PROMOTER SELECTIVITYCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 266. Nuclear and Cytoplasmic Functions of Abl Tyrosine KinaseINTRODUCTIONFUNCTIONAL DOMAINS OF ABLPROTEINS THAT INTERACT WITH ABLABL IN SIGNAL TRANSDUCTIONFUTURE PROSPECTSACKNOWLEDGEMENTREFERENCESChapter 267. Radiation Induced Cytoplasmic SignalingINTRODUCTIONPHYSICOCHEMICAL EFFECTS OF RADIATIONBIOLOGICAL TARGETS OF RADIATION RELEVANT FOR SIGNAL TRANSDUCTIONRIBOTOXIC STRESSREDOX SENSITIVE REGULATORY MOLECULESOTHER PATHWAYS OF UV MEDIATED CYTOPLASMIC SIGNALINGEXAMPLES OF RADIATION INDUCED SIGNAL TRANSDUCTIONOPEN QUESTIONSREFERENCESChapter 268. The Heat Shock Response and the Stress of Misfolded ProteinsINTRODUCTIONTRANSCRIPTIONAL REGULATION OF THE HEAT SHOCK RESPONSECHAPERONE FUNCTION IN NORMAL AND DISEASE STATESACKNOWLEDGEMENTSREFERENCESChapter 269. Hypoxia Mediated Signaling PathwaysINTRODUCTIONHIF REGULATIONHIF SIGNALING AND METASTASISUNFOLDED PROTEIN RESPONSECONCLUSIONSREFERENCESChapter 270. Regulation of mRNA Turnover by Cellular StressINTRODUCTIONRNA-BINDING PROTEINS CONTROLLING mRNA TURNOVERmRNA DECAY DETERMINANTS AND DEGRADATION MACHINERIESSTRESS-ACTIVATED SIGNALING MOLECULES THAT REGULATE mRNA TURNOVERCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 271. Oncogenic Stress ResponsesINTRODUCTIONDOWNSTREAM EFFECTORS OF OISp38MAPK SIGNALING AND OISDNA DAMAGE RESPONSE AND OISCONCLUDING REMARKSREFERENCESChapter 272. Ubiquitin and FANC Stress ResponsesINTRODUCTIONCOMPONENTS OF THE FANCONI ANEMIA PATHWAYTHE FA CORE COMPLEX AND ACTIVATION OF THE FA PATHWAYMONO-UBIQUITYLATION OF FANCD2 AND FANCIDOWNSTREAM EFFECTORS AND INTERACTIONS WITH OTHER DNA REPAIR PROTEINSDE-UBIQUITYLATION OF FANCD2 AND FANCINON-REPAIR FUNCTIONS OF THE FA PATHWAYCONCLUSIONREFERENCESChapter 273. Stress and γ-H2AXINTRODUCTIONSTRESS INDUCES DNA DSB DAMAGE AND γ-H2AX FORMATIONROLE OF γ-H2AX IN DNA DAMAGE REPAIR PATHWAYSγ-H2AX, A MARKER TO MONITOR CELL STRESS AND A PROTEIN INVOLVED IN STRESS SIGNALINGCONCLUSIONSACKNOWLEDGEMENTSREFERENCESSection D – Post-Transcriptional ControlChapter 274. Translational Control by Amino Acids and EnergyINTRODUCTIONTRANSLATIONAL CONTROL BY mTORC1REGULATION BY CELLULAR ENERGYREGULATION BY AMINO ACIDSREFERENCESChapter 275. Translation Control and Insulin SignalingINTRODUCTIONTHE INSULIN SIGNALING PATHWAYINSULIN SIGNALING AND REGULATION OF TRANSLATION INITIATIONINSULIN SIGNALING AND REGULATION OF TRANSLATION ELONGATIONINSULIN SIGNALING AND RIBOSOME BIOGENESISCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 276. ER and Oxidative Stress: Implications in DiseaseINTRODUCTIONUPR SIGNALINGIRE1 SIGNALINGPERK SIGNALINGATF6 SIGNALINGER STRESS INDUCED APOPTOSISER–MITOCHONDRIAL INTERACTIONSOXIDATIVE PROTEIN FOLDING IN THE ERER STRESS AND OXIDATIVE STRESS: IMPLICATIONS IN HUMAN DISEASEUPR AND OXIDATIVE STRESS IN METABOLIC DISEASENEURODEGENERATIVE DISEASESFUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 277. Regulation of mRNA TurnoverINTRODUCTIONCURRENT MODEL FOR MRNA DECAY IN MAMMALIAN CELLSDEADENYLATION: THE FIRST MAJOR STEP TRIGGERING MRNA DECAYREGULATION OF DEADENYLATION BY A PROTEIN THAT INTERACTS WITH BOTH POLYA) NUCLEASES) AND PABPA MECHANISM FOR TRANSLATIONALLY COUPLED MRNA TURNOVERTHE INVOLVEMENT OF RNA PROCESSING BODIES P-BODIES) IN REGULATION OF MRNA TURNOVERCONCLUDING REMARKSREFERENCESChapter 278. Signaling to Cytoplasmic Polyadenylation and TranslationINTRODUCTIONTHE BIOCHEMISTRY OF CYTOPLASMIC POLYADENYLATIONSIGNALING TO POLYADENYLATIONA HIERARCHY OF TRANSLATION CONTROLPOLYADENYLATION IN MAMMALIAN OOCYTESSIGNALING TO POLYADENYLATION IN THE BRAINCONCLUSIONSREFERENCESChapter 279. Translational Control in Invertebrate DevelopmentINTRODUCTIONTRANSLATIONAL CONTROL TARGETS OSKAR TO THE POLE PLASMTRANSLATIONAL CONTROL TARGETS NANOS TO THE POLE PLASMTHE HUNCHBACK GRADIENT IS ESTABLISHED BY TRANSLATIONAL CONTROLTRANSLATIONAL CONTROL IN THE DROSOPHILA NERVOUS SYSTEMNOS AND PUM REGULATE DENDRITE MORPHOGENESIS AND NEURONAL PLASTICITYTHE DROSOPHILA FRAGILE X GENE ENCODES A TRANSLATIONAL REPRESSOR THAT FUNCTIONS IN NEURON AND SYNAPSE DEVELOPMENT, AND ALSO IN THE GERM LINETRANSLATIONAL REPRESSION THROUGH MICRORNASROLE OF TRANSLATIONAL CONTROL IN REGULATING GROWTH4E-BP MEDIATED TRANSLATION REPRESSION IS CRITICAL UNDER STRESS CONDITIONSACKNOWLEDGEMENTREFERENCESChapter 280. The Role of Alternative Splicing During the Cell Cycle and Programmed Cell DeathINTRODUCTIONAPOPTOSIS AND SPLICINGCELL CYCLE AND SPLICINGCONCLUSIONSREFERENCESChapter 281. Signaling Pathways that Mediate Translational Control of Ribosome Recruitment to mRNAINTRODUCTIONTRANSLATION INITIATIONTHE eIF4F COMPLEXREGULATION OF TRANSLATION INITIATION BY mTORTRANSLATION AND CANCERCONCLUSIONSREFERENCESSection E – Chromatin and its ModificationChapter 282. The SWI/SNF and RSC Nucleosome Remodeling ComplexesINTRODUCTIONSTRUCTURE AND FUNCTION OF SWI/SNF AND RSCMODULATION OF ACTIVITY BY HISTONE MODIFICATIONSINVOLVEMENT OF SWI/SNF AND RSC IN DNA REPAIR AND GENOME STABILITYSPECIFIC ROLES OF SWI/SNF IN DNA DAMAGE REPAIRSPECIFIC ROLES OF RSC IN DNA DAMAGE REPAIRINVOLVEMENT OF SWI/SNF AND RSC IN TRANSCRIPTION ACTIVATIONINVOLVEMENT OF SWI/SNF AND RSC IN TRANSCRIPTION REPRESSIONINVOLVEMENT OF SWI/SNF IN TRANSCRIPTION MEMORYINVOLVEMENT OF SWI/SNF IN TRANSCRIPTION ELONGATIONREFERENCESChapter 283. ISWI Chromatin Remodeling ComplexesINTRODUCTIONBIOLOGICAL FUNCTIONS OF ISWI COMPLEXESMECHANISMS OF ISWI DEPENDENT CHROMATIN REMODELINGCONCLUSIONREFERENCESChapter 284. The INO80 Chromatin Remodeling ComplexINTRODUCTIONTHE INO80 COMPLEXREFERENCESChapter 285. Histone Acetylation ComplexesINTRODUCTIONKAT CLASSIFICATION AND DIVERSITYBROMODOMAINS AND OTHER INTERPRETERS OF HISTONE MODIFICATIONSKATS AND DISEASECONCLUSION AND FUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 286. Regulation of Histone Deacetylase Activities and Functions by Phosphorylation and DephosphorylationINTRODUCTIONREVERSIBLE PHOSPHORYLATION OF MAMMALIAN CLASS I HDACsREVERSIBLE PHOSPHORYLATION OF MAMMALIAN CLASS II HDACsCONCLUSION AND PERSPECTIVESREFERENCESChapter 287. Histone Methylation: Chemically Inert but Chromatin DynamicINTRODUCTIONHISTORICAL PERSPECTIVE OF CHROMATIN AND HISTONE METHYLATIONENZYMES REGULATING ARGININE AND LYSINE METHYLATION STATESHISTONE LYSINE METHYLTRANSFERASESHISTONE DEMETHYLASE ENZYMESDEGREE AND LOCATION MATTERREFERENCESChapter 288. Histone Phosphorylation: Chromatin Modifications that Link Cell Signaling Pathways to Nuclear Function RegulationINTRODUCTIONHISTONE PHOSPHORYLATION AND TRANSCRIPTIONAL REGULATIONDOWNSTREAM EFFECTS OF TRANSCRIPTION ASSOCIATED H3 PHOSPHORYLATIONHISTONE PHOSPHORYLATION IN RESPONSE TO DNA DAMAGEHISTONE PHOSPHORYLATION AND MITOSISHISTONE PHOSPHORYLATION DURING APOPTOSISHISTONE PHOSPHORYLATION AND HUMAN DISEASESCONCLUSIONS AND PERSPECTIVESREFERENCESChapter 289. Histone Variants: Signaling or Structural Modules?INTRODUCTIONH2A.Bbd IN SEARCH OF A FUNCTIONH2A.X: DNA DAMAGE AND BEYONDH2A.Z FUNCTION AT A FLIP OF A COINMACRO H2A: PHOSPHORYLATION MATTERSH2B VARIANCE AND UNKNOWN PARTNERSH3.3 PROVIDING TRANSCRIPTIONAL MEMORYCENP-A: SPLITTING NUCLEOSOMES IN DROSOPHILAHISTONE H1: THE MICRO-HETEROGENEITY OF SPECIALIZED FUNCTIONCONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 290. Silent Chromatin Formation and Regulation in the Yeast Saccharomyces cerevisiaeINTRODUCTIONSILENCER ELEMENTS AND SILENCER BINDING PROTEINSTHE SIR AND RENT SILENCING COMPLEXESTHE ROLE OF HISTONE MODIFICATIONS IN SILENT CHROMATIN FORMATIONASSEMBLY OF THE SIR COMPLEX AND SILENT CHROMATIN FORMATIONREGULATION OF SILENT CHROMATIN SPREADINGTHE NUCLEAR PERIPHERY AND SILENT CHROMATIN FORMATIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 291. Gene Silencing and Chromatin Modification by Polycomb Complexes in Flies and HumansINTRODUCTIONPHO-RC AND RECRUITMENT OF PcG COMPLEXES TO TARGET GENESPRC2ROLE OF H3-K27 METHYLATIONPRC1 AND POTENTIAL SILENCING MECHANISMSPcG PARTNERSHIP WITH OTHER CHROMATIN SILENCING ENZYMESPOLYCOMB SILENCING IN STEM CELL MAINTENANCEPOLYCOMB SILENCING COMPLEXES AND CANCERREFERENCESChapter 292. Histone UbiquitinationTHE MECHANISM OF UBIQUITINATIONHISTONE UBIQUITINATIONMONO-UBIQUITINATION OF H2AUBIQUITINATION OF HISTONE H2A VARIANTSDE-UBIQUITINATION OF UBH2AHOW DOES UBH2A REPRESS TRANSCRIPTION?THE ROLE OF UBH2A IN DNA REPAIRMONO-UBIQUITINATION OF H2BH2B UBIQUITINATION REQUIRES FACTORS INVOLVED IN TRANSCRIPTION INITIATION AND ELONGATIONH2B UBIQUITINATION IS REQUIRED FOR PROCESSIVE LYS-4 H3 AND LYS-79 H3 METHYLATIONTHE 19S PROTEASOME AND THE CCR4-NOT COMPLEX LINK H2B UBIQUITINATION TO LYS-4 AND LYS-79 H3 METHYLATIONDE-UBIQUITINATION OF UBH2BDE-UBIQUITINATION OF UBH2B IS REQUIRED FOR LATER STAGES OF TRANSCRIPTION ELONGATIONCONCLUSIONACKNOWLEDGEMENTREFERENCESChapter 293. Chromatin Mediated Control of Gene Expression in Innate Immunity and InflammationINTRODUCTIONINFLAMMATION AS A KINETICALLY COMPLEX TRANSCRIPTIONAL RESPONSECHROMATIN AND THE KINETIC CONTROL OF INFLAMMATORY RESPONSESGENETIC DISSECTION OF CHROMATIN REMODELING AT INFLAMMATORY GENESBINDING OF INFLAMMATORY TRANSCRIPTION FACTORS TO NUCLEOSOMAL DNACONCLUSIONSREFERENCESPart IV: Signaling from Intracellular CompartmentsINTRODUCTIONChapter 294. Protein Quality Control in the Endoplasmic ReticulumINTRODUCTIONER QUALITY CONTROLUNIQUE ENVIRONMENT OF THE ERMOLECULAR CHAPERONES AND FOLDING ENZYMEDISPOSAL OF UNFOLDED AND MISFOLDED PROTEINER SUBCOMPARTMENTSREFERENCESChapter 295. Quality Control and Quality Assurance in the MitochondrionINTRODUCTIONQUALITY ASSURANCE MEDIATED BY CHAPERONES AND THE PROTEIN TRANSLOCATION COMPLEXQUALITY CONTROL OF PROTEIN STRUCTURE AND FUNCTION MEDIATED BY ATP DEPENDENT PROTEASESPERSPECTIVEACKNOWLEDGEMENTSREFERENCESChapter 296. Protein Quality Control in Peroxisomes: Ubiquitination of the Peroxisomal Targeting Signal ReceptorsINTRODUCTIONPTS CO-) RECEPTOR UBIQUITINATION: CONUNDRUM AND CONFUSIONS. CEREVISIAE PEX18P IS DEGRADED IN AN UBIQUITIN DEPENDENT MANNERS. CEREVISIAE PEX5P, TWO DISTINCT UBIQUITINATION EVENTS, TWO DISTINCT FUNCTIONSTHE UBIQUITINATION OF P. PASTORIS PEX20P: TWO INDEPENDENT UBIQUITINATION EVENTS?INVOLVEMENT OF THE RING PROTEINS IN PTS CO-) RECEPTOR UBIQUITINATIONAAA PROTEIN MEDIATED CO-) RECEPTOR RECYCLING: AN UBIQUITIN DEPENDENT EVENT?CONCLUSIONSREFERENCESChapter 297. Mitochondrial Dynamics: Fusion and DivisionINTRODUCTIONMITOCHONDRIAL FUSIONMITOCHONDRIAL DIVISIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 298. The SREBP Pathway: Gene Regulation through Sterol Sensing and Gated Protein TraffickingSREBPS: MEMBRANE BOUND TRANSCRIPTION FACTORSSCAP: STEROL SENSOR AND ESCORTER OF SREBP FROM ER TO GOLGIINSIG: STEROL SENSOR AND ER RETENTION PROTEINSCAP AND INSIG: TWO SENSORS FOR TWO CLASSES OF STEROLSFUTURE CHALLENGESACKNOWLEDGEMENTSREFERENCESChapter 299. Regulating Endoplasmic Reticulum Function through the Unfolded Protein ResponseINTRODUCTIONMOLECULAR SENSORSHOW MOLECULAR SENSORS DETECT ER STRESSDOWNREGULATING THE UPRCELLULAR EFFECTS OF UPR INDUCTIONPHYSIOLOGICAL UPRPERSPECTIVESREFERENCESChapter 300. Signaling Pathways from Mitochondria to the Cytoplasm and NucleusINTRODUCTIONSMALL MOLECULES AS SIGNALS FROM MITOCHONDRIASMALL CATIONS: NA[sup+)], K[sup+)], MG[sup+2)], CA[sup+2)], H[sup+)]ATP, ADP, AND AMPNADH AND NAD[sup+)]GLUTATHIONE GSH AND GSSG)REACTIVE OXYGEN SPECIESIRON SULFUR CLUSTERSSIRTUINSMITOCHONDRIAL RETROGRADE SIGNALINGCONCLUSIONREFERENCESChapter 301. Apoptosis Signaling: A Means to an EndINTRODUCTIONTHE END OF THE ROADCASPASE-8 ACTIVATION VIA DEATH RECEPTORSMITOCHONDRIA AND THE ACTIVATION OF CASPASE-9MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATIONTHE BCL-2 FAMILYCELL CYCLE VERSUS APOPTOSISCONCLUSIONSREFERENCESChapter 302. Regulation of Cell Cycle ProgressionINTRODUCTIONCYCLINS DEFINE CELL CYCLE PHASESIGNALS TO SLOW PROGRESS: REGULATION OF CDKS BY INHIBITORY PROTEINSCDKS ARE POSITIVELY AND NEGATIVELY REGULATED BY PHOSPHORYLATIONDEGRADATION: THE IMPORTANCE OF BEING ABSENTCHECKPOINT SIGNALINGLESSONS FROM MICE: CELL DIVISION WITHOUT CDKSKNOCKOUT MOUSE MODELS: CYCLING WITHOUT CYCLINSREFERENCESChapter 303. Signaling During Organelle Division and Inheritance: PeroxisomesINTRODUCTION TO PEROXISOMESPEROXISOME DIVISIONPEROXISOME INHERITANCECONCLUDING REMARKSACKNOWLEDGEMENTSREFERENCESChapter 304. Signaling at the Nuclear EnvelopeINTRODUCTIONLAMINS AND LAMIN ASSOCIATED PROTEINS IN CELL SIGNALINGTHE NPC IN CELL SIGNALINGCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 305. Bidirectional Crosstalk between Actin Dynamics and EndocytosisINTRODUCTIONFROM ACTIN TO ENDOCYTOSISCONVERGING MOLECULAR MACHINERY IN ENDOCYTOSIS AND ACTIN DYNAMICSFROM ENDOCYTOSIS TO ACTIN DYNAMICSOUTLOOKACKNOWLEDGEMENTSREFERENCESChapter 306. Signaling in Autophagy Related PathwaysINTRODUCTIONSIGNALING CONTROL OF AUTOPHAGYAUTOPHAGY AND CELL DEATHACKNOWLEDGEMENTSREFERENCESPart V: Cell-Cell and Cell-Matrix InteractionsINTRODUCTIONChapter 307. Overview of Cell–Cell and Cell–Matrix InteractionsREFERENCESChapter 308. Interactive Signaling Pathways in the VasculatureINTRODUCTIONINTERACTIVE NETWORKS AS MODELS OF CELL SIGNALINGCROSS-TALK BETWEEN FGF AND NOTCH SIGNALINGNOVEL MODULATORS OF TGFβ SIGNALINGNOTCH, FGF, AND SMAD SIGNALING INTERACTIONSFEEDBACK INHIBITORY MECHANISMS IN VASCULAR CELL SIGNALINGIMPLICATIONS IN VASCULAR REMODELINGREFERENCESChapter 309. Signaling Pathways Involved in CardiogenesisINTRODUCTIONORIGIN OF CARDIOMYOCYTE PRECURSORSCARDIOMYOCYTE AND HEART TUBE FORMATIONCOMPLEX REGULATION OF CARDIAC MORPHOGENESISMOLECULAR REGULATION OF SEPTAL FORMATIONMICRORNA REGULATION OF CARDIOMYOCYTE DIFFERENTIATIONSUMMARYACKNOWLEDGEMENTSREFERENCESChapter 310. Regulatory Signaling in Pancreatic Organogenesis: Implications for Aberrant Signaling in Pancreatic CancerINTRODUCTIONNOTCH SIGNALING PATHWAYHEDGEHOG SIGNALING PATHWAYTRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAYWNT SIGNALING PATHWAYFIBROBLAST GROWTH FACTORS SIGNALING PATHWAYCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 311. Trophic Effects of Gut Hormones in the Gastrointestinal TractINTRODUCTIONTROPHIC EFFECTS OF GUT PEPTIDES IN THE STOMACH, SMALL BOWEL, AND COLONGI HORMONE RECEPTORS AND SIGNAL TRANSDUCTION PATHWAYSSIGNALING PATHWAYS MEDIATING THE EFFECTS OF INTESTINAL PEPTIDESCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 312. The Neurotrophin FactorsINTRODUCTIONNEURAL CELL DEATHTHE NEUROTROPHIC HYPOTHESISNEUROTROPHINSTHE NEUROTROPHIN RECEPTORSNEUROTROPHIN SIGNALING PATHWAYSTRANSCRIPTIONAL REGULATIONINTRACELLULAR TRAFFICKINGSUMMARYREFERENCESChapter 313. Cell to Cell and Cell-Matrix Interactions in BoneINTRODUCTION TO BONE AND BONE DISEASEDISEASES OF BONEBONE CELLS AND THEIR FUNCTIONSMECHANICAL STRAINHORMONES RESPONSIBLE FOR BONE DEVELOPMENT, GROWTH AND MAINTENANCEGROWTH, SIGNALING, AND TRANSCRIPTION FACTORS RESPONSIBLE FOR BONE DEVELOPMENT AND GROWTHBONE EXTRACELLULAR MATRIX ECM)CONCLUSION AND SUMMARYREFERENCESChapter 314. Cell-Cell Signaling in the Testis and OvaryINTRODUCTIONCELL–CELL SIGNALING IN THE TESTISCELL–CELL SIGNALING IN THE OVARYSUMMARYREFERENCESChapter 315. Signal Transduction in T LymphocytesINTRODUCTIONSIGNALING RECEPTORS IN T CELLS FORM DYNAMIC MACROMOLECULAR SIGNALING COMPLEXESCO-RECEPTOR AND CO-STIMULATORY PROTEINS MODULATE T CELL SIGNALING PATHWAYSINTRACELLULAR SIGNALING PATHWAYS INDUCED BY ANTIGEN STIMULATION OF T CELLSCONCLUSIONSREFERENCESChapter 316. Signal Transduction via the B Cell Antigen Receptor: A Crucial Regulator of B Cell BiologyINTRODUCTIONINITIATION OF SIGNAL TRANSDUCTION THROUGH THE BCRPROPAGATION OF SIGNAL TRANSDUCTION VIA THE BCRCONCLUSIONREFERENCESChapter 317. Signaling Pathways in the Normal and Neoplastic BreastINTRODUCTIONTHE EPIDERMAL GROWTH FACTOR FAMILYOTHER GROWTH FACTOR FAMILIESTHE PI 3-KINASE–AKT AND PTEN AXISCONCLUSIONSACKNOWLEDGEMENTSDEDICATIONREFERENCESChapter 318. KidneyOVERVIEW OF KIDNEY FUNCTION AND CELL-TO-CELL INTERACTIONSVASCULAR SMOOTH MUSCLE CELLSVASCULAR ENDOTHELIAL CELLSVASOACTIVE PARACRINE/AUTOCRINE AGENTS – ACTIONS IN THE RENAL VASCULATUREENDOTHELIAL CELL CONNECTIONS: CONNEXINS AND GAP JUNCTIONSPARACRINE SIGNALING IN RENAL-TUBULE EPITHELIAL CELLSINTERSTITIAL CELL–TUBULE COMMUNICATIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCESChapter 319. Cytokines and Cytokine Receptors Regulating Cell Survival, Proliferation, and Differentiation in HematopoiesisGENERAL ASPECTS OF HEMATOPOIESISHEMATOPOIETIC CYTOKINESSIGNALING THROUGH CYTOKINE RECEPTORSCONCLUDING STATEMENTSREFERENCESChapter 320. Signaling Pathways Regulating Growth and Differentiation of Adult Stem CellsINTRODUCTIONSTEM CELL PROPERTIESSIGNALING INTERMEDIATES AND PATHWAYS IN CD133 STEM CELLSCONCLUSIONSREFERENCESChapter 321. In Vivo Imaging of Cellular Network SignalingINTRODUCTIONIMPROVED METHODS TO MONITOR NETWORK SIGNALINGTWO-PHOTON MEASUREMENTS OF NEURAL NETWORK FUNCTIONFUTURE PERSPECTIVESREFERENCESPart VI: Disease Pathophysiology: Translational ImplicationsINTRODUCTIONChapter 322. The Roles of Ras Family Small GTPases in Breast CancerINTRODUCTIONRAS IN BREAST CANCERRHEBARHI/DI-RAS3/NOEY2RERGTHERAPEUTIC RE-EXPRESSION OF ARHI OR RERG IN BREAST CANCEROTHER RAS FAMILY PROTEINS IN BREAST CANCERREFERENCESChapter 323. Translational Implications of Stromal–Epithelial Interactions in Prostate Cancer and the Potential Role of Prostate Cancer Stem/Progenitor CellsINTRODUCTIONTHE PROSTATE TUMOR MICROENVIRONMENTPROSTATE DEVELOPMENT AND TISSUE ORGANIZATIONSTEM CELLSTUMOR STEM CELLSFIBROBLAST GROWTH FACTORHEDGEHOGTRANSFORMING GROWTH FACTOR BETAWNTOTHER PATHWAYSPROSTATE CANCER METASTASISSUMMARYREFERENCESChapter 324. Aberrant Signaling Pathways in Pancreatic Cancer: Opportunities for Targeted TherapeuticsINTRODUCTIONONCOGENIC ACTIVATION IN PDACLOSS OF TUMOR SUPPRESSOR FUNCTION IN PDACBMPsCONTRIBUTIONS OF PANCREATIC STROMA AND STROMAL COMPONENTS IN PDACDIFFERENTIATIONAPOPTOTIC PATHWAYS AND APOPTOTIC RESISTANCECLINICAL ASPECTS OF PDACCONCLUSIONSACKNOWLEDGEMENTREFERENCESChapter 325. The Evolution and Maintenance of the Multiple Myeloma Cell Clone within the Liquid Bone Marrow Compartment: Therapeutic ImplicationsINTRODUCTIONTHE GENETIC BACKGROUND OF MM CELLS AND DYSREGULATED SIGNALING MOLECULESCD138 AND SIGNALING PATHWAYS ASSOCIATED WITH THE PUTATIVE MM STEM CELLSIGNALING PATHWAYS ACTIVATED IN THE MM BONE MARROW MICROENVIRONMENTCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 326. The Pathophysiologic Role of the Bone Marrow Environment and its Niches in Multiple MyelomaINTRODUCTIONTHE BM NICHESSIGNALING PATHWAYS TRIGGERED BY THE INTERACTION OF MM CELLS WITH BMSCS AND THE ECM OF THE BM MICROENVIRONMENTBIOLOGICALLY BASED TARGETED THERAPIESCONCLUSIONACKNOWLEDGEMENTSREFERENCESChapter 327. Signaling Targets in Myeloid LeukemiasINTRODUCTIONMOLECULAR HETEROGENEITY OF MYELOID LEUKEMIASGENE ABNORMALITIES THAT CONFER PROLIFERATIVE AND/OR SURVIVAL ADVANTAGEGENE ABNORMALITIES THAT BLOCK MYELOID DIFFERENTIATIONCML–A PARADIGM FOR SIGNAL TRANSDUCTION BIOLOGYCML: A PARADIGM FOR SIGNAL TRANSDUCTION THERAPEUTICSAML: IN SEARCH OF TARGETED THERAPIESDRUGS TARGETING TRANSCRIPTION FACTORSDRUGS TARGETING CELL SURFACE MOLECULESFUTURE PERSPECTIVEREFERENCESChapter 328. Signaling Targets in Lymphoid LeukemiasINTRODUCTIONMOLECULAR HETEROGENEITY OF LYMPHOID LEUKEMIASCHRONIC LYMPHOCYTIC LEUKEMIA IS A B CELL DISEASEDRUG TARGETS IN LYMPHOID LEUKEMIASKINASE INHIBITORSTHERAPIES TARGETING CELL SURFACE ANTIGENSDRUGS TARGETING TRANSCRIPTION FACTORSFUTURE DIRECTIONSREFERENCESChapter 329. Targeting Ras for Anticancer Drug DiscoveryINTRODUCTIONRAS PROTEINS FUNCTION AS SIGNALING NODESRAS ACTIVATION IN HUMAN CANCERS: VALIDATION AND DRUGGABILITYTARGETING RAS MEMBRANE ASSOCIATIONTARGETING RAS EFFECTOR SIGNALINGINHIBITORS OF PI3K-AKT-MTOR SIGNALINGINHIBITORS OF OTHER RAS EFFECTOR PATHWAYSCONCLUSIONS AND FUTURE DIRECTIONSACKNOWLEDGEMENTSREFERENCESChapter 330. Targeting EWS/FLI1 Driven Signaling Pathways as Therapy for Tumors of the Ewings Sarcoma FamilyABBREVIATIONSEWING’S SARCOMA: CLINICAL ASPECTS AND MOLECULAR LANDMARKSTRANSCRIPTIONAL TARGETS OF EWS/FLI1: IDENTIFICATION OF CAVEOLIN-1 AS A KEY DETERMINANT OF THE NEOPLASTIC PHENOTYPE OF EWS CELLSCAV1 DOWNREGULATION INHIBITS THE GROWTH OF EWS TUMOR IN VIVOCAV1 DOWNREGULATION SENSITIZES EWS CELLS TO CHEMOTHERAPEUTIC TREATMENT BY A MECHANISM INVOLVING PKCαINVOLVEMENT OF mTOR IN THE RESPONSE OF EWS CELLS TO IONIZING RADIATIONEFFECT OF JUNCTION TARGETED ANTISENSE OLIGONUCLEOTIDES, ALONE OR IN COMBINATION WITH RAPAMYCIN, ON EWS CELLS IN VITRO AND IN VIVODETERMINANTS OF THE IR RESPONSE OF EWS CELLS AND ESFTCAV1 IS A KEY DETERMINANT OF THE SENSITIVITY OF EWS CELLS TO IRPLD2 INTERACTS WITH CAV1 AND PKCα IN EWS CELLS AND PARTICIPATES IN THEIR RESPONSE TO IRSTUDIES RELATED TO THE REGULATION OF PARP-1 IN EWS CELLSINDUCTION OF APOPTOSIS IN EWS CELLS BY CYCLIN DEPENDENT KINASE INHIBITIONACKNOWLEDGEMENTSREFERENCESChapter 331. IRS-Protein Scaffolds and Insulin/IGF Action in Central and Peripheral TissuesINTRODUCTIONINSULIN, IGFS, AND THEIR RECEPTORSINSULIN RECEPTOR SUBSTRATESDYSREGULATION OF IRS-PROTEIN SIGNALINGSUMMARY AND PERSPECTIVESREFERENCESChapter 332. Adipokine Signaling: Implications for ObesityADIPOSE TISSUE AND ITS RELATION TO OBESITYLEPTINADIPONECTINPROINFLAMMATORY CYTOKINESOTHER ADIPOKINES RELATED TO OBESITYCONCLUDING REMARKSACKNOWLEDGEMENTREFERENCESChapter 333. Angiogenesis Signaling Pathways as Targets in Cancer TherapyINTRODUCTIONOVERVIEW OF ANGIOGENESIS AND ITS ROLE IN TUMOR DEVELOPMENTTUMOR VESSEL STRUCTURETUMOR STROMA AND THE EXTRACELLULAR MATRIXTHE ROLE OF HYPOXIA IN REGULATING TUMOR ANGIOGENESISOVERVIEW OF CRITICAL PATHWAYS INVOLVED IN STIMULATING ANGIOGENESISTHE ROLE OF CYTOKINES IN ANGIOGENESISTHE ANGIOPOIETINS AND THE ANGIOGENIC SHIFTANGIOGENESIS INHIBITORSANTI-ANGIOGENESIS APPROACHES AND TREATMENTSIMPLICATIONS OF TARGETING ANGIOGENESIS–ADVANTAGES AND DISADVANTAGESCONCLUSIONSACKNOWLEDGEMENTREFERENCESChapter 334. CXC Chemokine Signaling in Interstitial Lung DiseasesINTRODUCTIONCHEMOKINE REGULATION OF ANGIOGENESIS IN PULMONARY FIBROSIS: RECIPROCAL ROLES OF CXCR2 AND CXCR3MESENCHYMAL PROGENITORS IN PULMONARY FIBROSIS: ROLE OF CXCR4POTENTIAL THERAPEUTIC APPLICATIONS OF CHEMOKINE SIGNALINGCONCLUSIONSACKNOWLEDGEMENTREFERENCESChapter 335. Systemic SclerosisINTRODUCTIONPATHOGENESIS OF SSC: AN INTEGRATED OVERVIEWINSIGHTS FROM GENETIC AND EPIDEMIOLOGIC STUDIESSOLUBLE FACTORS THAT MODULATE FIBROSISOTHER GENES IMPLICATED IN SSCANIMAL MODELS OF SCLERODERMACONCLUSIONSREFERENCESChapter 336. Signal Transduction in Rheumatoid Arthritis and Systemic Lupus ErythematosusINTRODUCTIONSTAT4 RS7574865 ALLELE AND THE RISK OF RATNFR1 AND C5 RS376147 AND RS2900180) AND THE RISK OF RACHALLENGES TO THE APPLICATION OF FINDINGS FROM GENETIC MAPPING STUDIES TO CLINICAL CONSEQUENCESPTPN22CTLA4IL4R VARIANTS I50V AND Q551R AND RATLR SIGNALING AND ARTHRITIS AND AUTOIMMUNITYNFκB SIGNALING IN ARTHRITIS AND INFLAMMATIONB CELL SIGNALING IN AUTOIMMUNITYCD22PD-1SHP-1SHIPSUMMARYREFERENCESChapter 337. Translational Concepts in VasculitisINTRODUCTIONMECHANISMS IN THE PATHOGENESIS OF VASCULITISTRANSLATIONAL APPROACHES TO THERAPEUTICS IN VASCULITISCLASSIFICATION OF VASCULITIC SYNDROMESCONCLUSIONSREFERENCESChapter 338. Advances in Understanding the Pathogenesis of Inflammatory Bowel DiseaseINTRODUCTIONMUCOSAL INTEGRITYROLE OF T CELL LINEAGE IN PATHOGENESIS OF IBDREGULATORY T CELLSROLE OF SIGNALING IN IBD PATHOGENESISEPITHELIAL CELLS, IFNγ, AND THEIR IMPACT ON IBDTOLL-LIKE RECEPTORS AND OTHER ENVIRONMENTAL STIMULI: PUTTING IT TOGETHERGENETICS OF INFLAMMATORY BOWEL DISEASENEW THERAPEUTIC OPTIONSFUTURE THERAPIESCONCLUSIONREFERENCESChapter 339. Translational Implications of ProteomicsINTRODUCTIONPROFILING OF TISSUES TO IDENTIFY POTENTIAL CIRCULATING MARKERSPROTEOMIC PROFILING OF PROXIMAL BIOLOGICAL FLUIDSPROFILING OF TUMOR CELL POPULATIONSPROFILING THE PLASMA PROTEOME FOR CANCER BIOMARKER IDENTIFICATIONPOSTTRANSLATIONAL MODIFICATIONS AS A SOURCE OF CANCER BIOMARKERSMICROARRAY BASED APPROACHES FOR BIOMARKER IDENTIFICATIONVALIDATION STRATEGIES FOR DISCOVERED PROTEIN BIOMARKERSREFERENCESChapter 340. Translational Implications of microRNAs in Clinical Diagnostics and TherapeuticsBIOGENESIS AND FUNCTIONS OF ANIMAL MICRORNASMICRORNAS IN PHYSIOLOGICAL AND METABOLIC PROCESSESMICRORNAS IN HUMAN DISEASEMICRORNAS IN HUMAN CANCERMICRORNAS AND VIRAL LIFE CYCLESFUTURE MICRORNA BASED THERAPEUTIC STRATEGIESCONCLUSIONSACKNOWLEDGEMENTSREFERENCESIndexABCDEFGHIJKLMNOPQRSTUVWXYZ
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