信号转导及其异常课件

AberrantCellSignalingandtheRelatedDisordersDisordersofsignaltransductionsystemsCauses

Genemutation--Functionlossorgain

ChangeofquantityofsignalproteinsChangeofactivityofsignalproteins

Autoimmunediseases

SecondarychangesAbnormality:

Ligands,Receptors,Post-receptorpathways,EffectorsDown-regulation/interruptionofsignalingSignalInsufficiencyReceptorsdown-regulation/desensitization:decreasedquantity,bindingaffinity,inhibitoryAb,cofactordisorders,functionloss,etc.DefectsinAdaptors,Signaltransducers,Effectors(Enzymes,Transcriptionfactors,etc)Up-regulation/over-activationofsignalingSignalExcessReceptorup-regulation,hypersensitivity,stimulatoryAb,etcSignaltransducers,TFs:over-expression,persistentactivationOthersPathogenesisanddiseases1.AberrantSignalViralinfectionsorotherdamagestopancreatic-cellinsulinproduction

hyperglycemia

Diabetes(TypeI)(1)AberrantSignal(SignalInsufficiency)Insulinreceptor(IR):heterotetramer(2

,2

)InsulinbindingleadstochangeinconformationActivatesIR-subunitPTKactivity

-subunitphosphorylatesTyrresiduesoncytoplasmicdomainsaswellasdownstreamsubstrates(IRS)ischemia,epilepsy,neurodegenerativediseasesextracellularglutamate/asparticacid

NMDARactivation(N-methyl-D-aspartatereceptor,IonChannelLinkedReceptor)Ca2+influx[Ca2+]i,activationofenzymesexcitatoryintoxication(2)AberrantSignal(SignalExcess)（1）ReceptorGeneMutation

—Geneticinsulin-resistantdiabetes

IRgenemutations

DisturbancesinsynthesistransfertothemembraneaffinitytoinsulinPTKactivityproteolysisTypeIIDiabetesInsulin+IRActivateRPTKIRSPI3KRas/Raf/MEK/ERKGlycogenSynthesis,CellTransportproliferation&UtilizationBindingofTSHtoR↓hypothyroidism(2)Autoimmunediseases-thyropathyBlockingAbTSH-R295~302385~395residuesGsACcAMPThyroidproliferation&secretionofthyroxine

GqPLCIP3DAGCa2+PKCTSH-R（GPCR)30~35residues

StimulatoryAbhyperthyroidismGraves病（弥漫性毒性甲状腺肿）刺激性抗体模拟TSH的作用促进甲状腺素分泌和甲状腺腺体生长女性>男性甲亢、甲状腺弥漫性肿大、突眼桥本病(Hashimoto’sthyroditis,慢性淋巴细胞性甲状腺炎)阻断性抗体与TSH受体结合减弱或消除了TSH的作用抑制甲状腺素分泌甲状腺功能减退、黏液性水肿(3)SecondaryAbnormalityinReceptorsHeartfailure,Myocardialhypertrophy

-adrenergicreceptors(GPCR)downregulatedordesensitizedReactiontocatecholamines

Myocardialcontraction

AlleviateAcceleratemyocardiallesionheartfailure

分类累及的受体主要临床特征遗传性受体病

膜受体异常家族性高胆固醇血症

LDL受体

血浆LDL升高，脂质代谢紊乱，动脉粥样硬化家族性肾性尿崩症ADHV2型受体(GPCR)男性发病，多尿、口渴和多饮

c视网膜色素变性视紫质进行性视力减退Cccccccccccccccc遗传性色盲视锥细胞视蛋白色觉异常11111111111111严重联合免疫缺陷症IL-2受体γ链T细胞减少或缺失，反复感染CcccccccccccccccII型糖尿病胰岛素受体(RTK)

高血糖,血浆胰岛素正常或升高ccc核受体异常

ccc雄激素抵抗综合征雄激素受体不育症，睾丸女性化cccccccccccccccc维生素D抵抗性佝偻病维生素D受体佝偻病骨损害，秃发，继发性甲状旁腺素增高Cccccccccccccccc甲状腺素抵抗综合征β甲状腺素受体甲状腺功能减退，生长迟缓cccccccccccccccc雌激素抵抗综合征雌激素受体骨质疏松，不孕症Ccccccccccccccc糖皮质激素抵抗综合征糖皮质激素受体多毛症,性早熟,低肾素性高血压受体异常疾病自身免疫性受体病

cccccccccccccccc重症肌无力

nAch受体活动后肌无力cccccccccccccccc自身免疫性甲状腺病刺激性TSH受体(GPCR)

抑制性TSH受体甲亢和甲状腺肿大

甲状腺功能减退ccccccccccccccccII型糖尿病胰岛素受体高血糖，血浆胰岛素正常或升高cccccccccccccccc艾迪生病ACTH受体色素沉着，乏力，血压低继发性受体异常

ccccccccccccccc心力衰竭

肾上腺素能受体

心肌收缩力降低ccccccccccccccc帕金森病多巴胺受体肌张力增高或强直僵硬ccccccccccccccc肥胖胰岛素受体血糖升高ccccccccccccccc肿瘤生长因子受体细胞过度增殖3.AberrantG-proteininCellSignalingGs

genemutationGTPaseactivityPersistentactivationofGs

PersistentactivationofACcAMPPituitaryproliferationandsecretionGHRHPituitaryGHRH-RGs

Ac,cAMPGHAcromegalyorGigantism(1)G-proteingenemutation—pituitary

tumor(2)G-proteinmodification——choleraCholeratoxinGs

ribosylationatArg201InactivationofGTPasePersistentactivationofGs

andAc,cAMPConformationalalterationofintestinalepitheliaCl-andH2OtolumenofintestineDiarrheaanddehydrationCirculationfailure

Theintracellularsignalinginvolvesvariousmessengers,transducers,andtranscriptionfactors.

Disorderscanoccurinanyofthesesettings.--Calciumoverloadisageneralpathologicalprocessinvariousdiseases;--ThelevelofNOispositivelycorrelatedwithischemicinjury;--StimulationofNF-

Bisseeninvariousinflammatoryresponses4.AberrantintracellularSignalingPro-carcinogenofphorbolester（diglyceride(DG)analogy）PKCpersistentactivationGrowthfactorsCancergeneexpressionNa+/H+exchange

IntracellularpH↑/K+↑Cellproliferation(Cancer)AberrantintracellularSignaling佛波酯型促癌物5.

MultipleAbnormalitiesinSignalingPathwayCancer,asetofdiseasescharacterizedbyuncontrolledorinappropriatecellgrowth,isstronglyassociatedwithdefectsinsignal-transductionproteins.Ligands(GFs):e.g.EGFReceptors(overexpression,activationofTPK):e.g.EGFRIntracellularsignaltransducers：

RasgenemutationRas-GTPaseRasactivationRafMEKERKProliferationTUMORMultifactorAberranciesandCancer---EnhancementofproliferatingsignalsMultifactorAberranciesandCancer---Deficitsinproliferation-inhibitingsignalTGF-

+TGF-RPSTKactivationSmad-phosphorylationP21/P27/P15expressionCdk4inhibitionCellcyclearrestsatG1phaseInhibitscellproliferation(pro-apoptosis)Lymphoma,livercancer,StomachcancerGenemutationNegativeregulation6.SameStimulantInducesDifferentResponses(thesamestimulicanactondifferentreceptors)7.DifferentSignalsInducestheSamePathologicResponse(differentreceptorsusethesamepathwayorbycross-talk)DifferentreceptorsusesamepathwaysGPCR,RTK,CytokinesRsPLCRasPI-3KPKCRafPKBMEKERKCrosstalk—howhypertensionleadstomyocardialhypertrophy?NE,AT-IIPLCCa2+/PKCMechanicstimuliNa+