信號轉(zhuǎn)導異常與疾病

1、 Department of Department of PathophysiologyPathophysiology guangdong guangdong Medical College Medical CollegeA.A.CarlssonCarlsson 2000G.G.Blobel 1999Nobel prizes awarded for research Nobel prizes awarded for research in signal in signal transductiontransductionR.Furchgott 1998 A.A.Gilman 1994qIntr

2、oduction qRegulation of CSTqMembranous receptors- medicated CSTqAbnormality of CST and diseaseqIntroduction Why?Why?What?What?How?How?synaptic cleftdirect contactindirect contact 細胞信號轉(zhuǎn)導細胞信號轉(zhuǎn)導 cellular signal transduction LigandReceptorTransducerEffector The process in which cells recept the extracel

3、lular stimuli through membranous or intracellular receptors, transduce the signals via intracellular molecules, and thus regulate the biological function of the cells.LigandEffectorReceptorTransducerextracellular stimuli 1)Physical signals light, electronic, mechanic, UV, heat, volume or osmotic, et

4、c 2) Chemical signals hormones, neurotransmitters, GFs, cytokines; odor molecules; ATP, active oxygen; drugs, toxins, etcsignalssignalsLigand General process for signal transduction跨膜信號轉(zhuǎn)導跨膜信號轉(zhuǎn)導 transmembrane signal transduction The process in which cells recept the extracellular stimuli through memb

5、ranous or intracellular receptors, transduce the signals via intracellular molecules, and thus regulate the biological function of the cells The process in which cells recept the extracellular stimuli through membranous or intracellular receptors, transduce the signals via intracellular molecules, a

6、nd thus regulate the biological function of the cells.membranous receptornuclear receptor vion-channel receptorvG-protein coupled receptorvtyrosine protein kinase receptor steroid hormone receptor thyrine receptorLigandEffectorReceptorTransducerReceptoro Regulation of ligando Regulation of G-Protein

7、o Regulation of phosphorylateLigandEffectorReceptorTransducerTransducerRegulation of ligand regulation of phosphorylate Pi H2OATP ADP蛋白質(zhì)蛋白質(zhì)磷酸化蛋白質(zhì)磷酸化蛋白質(zhì)蛋白激酶蛋白激酶蛋白磷酸酶蛋白磷酸酶Growth factorsRaf MEK ERK ProliferationDifferentiationCell survival Cytokines Cellular stressMEKK MKKJNK/p38 InflammationCell death

8、stimuliMAPKKKMAPKKMAPKResponse enzyme ion channelcytoskeletal proteinLigandEffectorReceptorTransducerEffectortranscription factortransport proteinqRegulation of CSTqMembranous receptors- medicated CSTqAbnormality of CST and diseaseqMembranous receptors- medicated CSTqIntroduction qMembranous recepto

9、rs-medicated CSTvG G蛋白偶聯(lián)受體蛋白偶聯(lián)受體介導的信號途徑介導的信號途徑 （G-protein coupled receptorG-protein coupled receptor，GPCRGPCR）v 酪氨酸蛋白激酶酪氨酸蛋白激酶介導的信號途徑介導的信號途徑 (tyrosine protein kinase ,TPK)特征特征: :需借助需借助G-G-蛋蛋白的作用白的作用o肽鏈，七個肽鏈，七個-螺旋反復穿過細胞膜螺旋反復穿過細胞膜o氨基酸組成不同導致配體特異性氨基酸組成不同導致配體特異性o細胞內(nèi)部有細胞內(nèi)部有G-G-蛋白結合點蛋白結合點G-protein coupled

10、receptorG-protein coupled receptoro Definitiono ConstructionG-ProteinsGPCR pathway 能與鳥嘌呤核苷酸可逆性能與鳥嘌呤核苷酸可逆性結合的蛋白質(zhì)家族。結合的蛋白質(zhì)家族。G-G-ProteinGDPGDPGTPGTPGTPGTPGTPGTPGTPGTPGTPGTPinhabit ACactivate ACactivate PLCactivate RhoGPCR pathwayo Definitiono ConstructionG-ProteinsGPCR pathwayo Regulation of G-Protein

11、Regulation of G-ProteinGTPinactivationactivationvG G蛋白偶聯(lián)受體蛋白偶聯(lián)受體介導的信號途徑介導的信號途徑 （G-protein coupled receptorG-protein coupled receptor，GPCRGPCR）1. Adenylate Cyclase pathway2. IP3、Ca2+-Calmodulin pathway3. DAG-PKC PathwayGPCR pathway ( (一一) ) 腺苷酸環(huán)化酶途徑腺苷酸環(huán)化酶途徑( (ACAC途徑）途徑） Adenylate Cyclase pathway ACAC

12、 GPCR-mediated CSTGPCR-mediated CST -R 2-R，M-R GsGs GiGi AC cAMP PKA protein genephosphorylation transcription-+(二) IP3、Ca2+-Calmodulin pathwayGPCR pathwayPIP2 GPCR-mediated CSTGPCR-mediated CST -R 2-R，M-R 1-R，ET-R GsGs GiGi GqGq AC PLC cAMP PIP2 IP3 PKA Ca2+ release protein gene phosphorylation tra

13、nscription+-GPCR pathwayPIP2PKC(三三) DAG-PKC Pathway GPCR-mediated CSTGPCR-mediated CST -R 2-R，M-R 1-R，ET-R GsGs GiGi GqGq AC PLC cAMP PIP2 IP3 PKA DAG Ca2+ release protein gene PKC protein phosphorylation transcription phosphorylationSummary+-+v 酪氨酸蛋白激酶介導的信號途徑酪氨酸蛋白激酶介導的信號途徑 (一一) 酪氨酸蛋白激酶酪氨酸蛋白激酶受體受體途徑

14、途徑 (tyrosine protein kinase receptor pathway，TPKR) (二二) 非酪氨酸蛋白激酶非酪氨酸蛋白激酶受體受體途徑途徑 (non-tyrosine protein kinase receptor pathway) q Membranous receptors-medicated CSTtyrosine protein kinase receptortyrosine kinase domainstyrosine phosphorylationsites(一一) 酪氨酸蛋白激酶受體酪氨酸蛋白激酶受體途徑途徑 (tyrosine protein kinase

15、 receptor pathway，TPKR) 1. Ras-MAPK pathway 2. Phospholipase C pathway 3. PI-3K pathway1.Tyrosine kinase receptors are a family of receptors with a similar structureTPKR pathway2.When the receptors aggregate, the C terminal tyrosine residues is phosphorylated.TPKR pathway3.This phosphorylation produ

16、ces binding sites for proteins with SH2 domains. GRB2 is one of these proteins. This causes the activation of SOS.TPKR pathway4. SOS is a guanyl nucleotide-release protein (GNRP). When ras has GTP bound to it, it becomes active. TPKR pathway5. Activated ras causes the activation of a cellular kinase

17、 called raf-1. Raf-1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK. TPKR pathway6.Activated MEK phosphorylates MAPK. This series of phosphylating activations is called a kinase cascade. TPKR pathway7. Phosphorylation of transcriptions factors causes

18、them to become active and bind to the DNA, causing changes in gene transcriptionTPKR pathwaytyrosine protein kinase receptor PI3KGFTPK靶蛋白靶蛋白磷酸化磷酸化Grb2SosRafMEKERK靶蛋白靶蛋白磷酸化磷酸化轉(zhuǎn)錄因子轉(zhuǎn)錄因子磷酸化磷酸化靶基因靶基因轉(zhuǎn)錄轉(zhuǎn)錄PLC PIP2DAGPKCIP3Ca2+50 kindsRasSummaryTPKR pathway構型改變構型改變G蛋白活化蛋白活化效應酶磷酸化效應酶磷酸化配體與受體結合配體與受體結合激活細胞內(nèi)蛋白激

19、酶激活細胞內(nèi)蛋白激酶第二信使生成第二信使生成靶蛋白磷酸化靶蛋白磷酸化靶基因轉(zhuǎn)靶基因轉(zhuǎn) 錄錄配體與受體結合配體與受體結合構型改變構型改變酪氨酸激酶活化酪氨酸激酶活化激活細胞內(nèi)蛋白激酶激活細胞內(nèi)蛋白激酶靶蛋白磷酸化靶蛋白磷酸化靶基因轉(zhuǎn)靶基因轉(zhuǎn) 錄錄TPKR pathwayTPKR TPKR 途徑與途徑與GPCRGPCR途徑區(qū)別途徑區(qū)別v 酪氨酸蛋白激酶介導的信號途徑酪氨酸蛋白激酶介導的信號途徑 (一一) 酪氨酸蛋白激酶酪氨酸蛋白激酶受體受體途徑途徑 (tyrosine protein kinase receptor pathway，TPKR) (二二) 非酪氨酸蛋白激酶非酪氨酸蛋白激酶受體受體途徑

20、途徑 (non-tyrosine protein kinase receptor pathway) q Membranous receptors-medicated CST胞外區(qū)胞外區(qū)跨膜區(qū)跨膜區(qū)胞內(nèi)區(qū)胞內(nèi)區(qū)(二二)非酪氨酸蛋白激酶受體途徑非酪氨酸蛋白激酶受體途徑 (non-tyrosine protein kinases receptor pathway)JAKJAKSTATSTATSTATSTATR R二聚化二聚化STATSTAT結合結合STATSTAT二聚化二聚化基因轉(zhuǎn)錄基因轉(zhuǎn)錄JAKJAKq膜受體介導的信號轉(zhuǎn)導通路膜受體介導的信號轉(zhuǎn)導通路v酪氨酸蛋白激酶介導的信號途徑酪氨酸蛋白激酶介導

21、的信號途徑vG G蛋白介導的信號途徑蛋白介導的信號途徑(一一) 腺苷酸環(huán)化酶途徑腺苷酸環(huán)化酶途徑(二二) IP3、Ca 2+-鈣調(diào)蛋白激酶途徑鈣調(diào)蛋白激酶途徑(三三) DAG-蛋白激酶蛋白激酶C途徑途徑( (一一) ) TPKRTPKR途徑途徑( (二二) )非非TPKRTPKR途徑途徑different receptors-mediated pathways interact by cross-talkqRegulation of CSTqMembranous receptors- medicated CSTqAbnormality of CST and diseaseqRegulation

22、 of CSTqIntroduction Homology regulation Heterology regulationvup regulation vdown regulation配體配體變化導致變化導致特異特異結合的受體結合的受體數(shù)量發(fā)數(shù)量發(fā)生變化生變化受體數(shù)目增加受體數(shù)目增加q Regulation of receptor數(shù)量數(shù)量親和力親和力 ( (qRegulation of receptor LigandProtein kinaseResponseP PP P抑制蛋白抑制蛋白P PP P抑制蛋白抑制蛋白P P 低pH受體去磷酸化受體去磷酸化PKAGRK內(nèi)吞內(nèi)吞再循環(huán)再循環(huán)溶酶體溶

23、酶體降解降解E2 2腎上腺受體的磷酸化、內(nèi)吞和再循環(huán)腎上腺受體的磷酸化、內(nèi)吞和再循環(huán)qRegulation of CSTqMembranous receptors- medicated CSTqAbnormality of CST and diseaseqAbnormality of CST and diseaseqIntroduction Ligand normalReceptor normalTransducer normalEffector normalBiologyHeredityImmunityInternal environmentProliferationDifferentiat

24、ionApoptosisMigration v Causes and mechanismsLigand abnormalReceptor abnormalTransducer abnormalEffector abnormalqAbnormality of CST and diseasev Causes and mechanismsv Aberrant receptors and diseases v Aberrant G-proteins and diseases v Multiple signaling aberrations and diseasesqAbnormality of CST

25、 and diseasev Aberrant receptors and diseases 遺傳性受體病（基因突變）遺傳性受體?。ɑ蛲蛔儯┚幋a受體的基因突變而引起的疾病。編碼受體的基因突變而引起的疾病。免疫性受體病免疫性受體病 受體數(shù)量改變（缺失、減少）受體數(shù)量改變（缺失、減少） 受體功能改變（失活性突變）受體功能改變（失活性突變）o 胰島素抵抗性糖尿病胰島素抵抗性糖尿病o 雄激素抵抗征雄激素抵抗征o 家族性尿崩癥家族性尿崩癥v Aberrant receptors and diseases 遺傳性受體遺傳性受體病病o 家族性尿崩癥家族性尿崩癥 ( P108)水水 通通 道道蛋白改變蛋白改變

26、通透性通透性GscAMPPKAADH微絲管微絲管磷酸化磷酸化o 家族性尿崩癥家族性尿崩癥 ( P108)遺傳性受體遺傳性受體病病中樞性尿崩癥中樞性尿崩癥免疫性受體病免疫性受體病o 自身免疫性的甲狀腺病自身免疫性的甲狀腺病(P107)TSHRGraves橋本病橋本病GsACcAMPPKCDGPLC RasRafERK甲狀甲狀腺素腺素v Cause and mechanismsv Aberrant receptors and diseases v Aberrant G-proteins and diseases v Multiple signaling Aberrations and diseas

27、esqAbnormality of CST and diseasev Aberrant G-proteins and diseases 霍亂霍亂 P106 巨人癥與肢端肥大癥巨人癥與肢端肥大癥 P110v Aberrant G-proteins and diseases 巨人癥與肢端肥大癥巨人癥與肢端肥大癥(GH ) P110Gs cAMPAC活性活性GHGHRHRAdult？Child？基因點突變基因點突變v Causes and mechanismsv Aberrant receptors and diseases v Aberrant G-proteins and diseases v

28、Multiple signaling aberrations and diseasesqAbnormality of CST and diseasesv Multiple signaling aberrations anddiseases 腫瘤腫瘤 P110v Multiple signaling aberrations and diseasesnLigands (GFs) nReceptors overexpressionntransducers activation1) Increase of proliferating signalsTPKGFPI3KPKBPKBRasRafERKPLC Gene transcriptionPKCv腫瘤腫瘤 P110TGF- + TGF- RPSTK activationSmad-phosphorylationP21/P27/P15 expressionCdk4 inhibitionCell cycle arrests at G1 phaseInhibits cell proliferation (pro-apoptosis)Lymphoma, live