细胞信号转导英文版

1、 Chapter 15Cellular Signal TransductionThe biochemistry and molecular biology department of CMUWhen environment changes: Monadresponds directly.Multicellular organismssignal through elaborate system of intercellular or intracellular communication，and consequently regulate functions of organisms.Sign

2、aling moleculeReceptor of target cellIntracellular moleculebiological effectSignaltransduction 1 Signaling MoleculesSignaling molecules Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular respons

3、es. Extracellular molecules Intracellular molecules 1. Extracellular moleculesprotein & peptides: Hormone, cytokineAA & its derivatives: Gly, Glu, adrenaline, thyroxineSteroid: Sex Hormone, glucocorticosteroidFatty acid derivatives: prostaglandin (1) Paracrine signaling (local chemical media

4、tors) Secreted by common cells. Reach neighboring target cells by passive diffusion. Time of action is short. Such as GF, PG(2) Endocrine signal Secreted by endocrine cells. Reach target cells by blood circulation. Time of action is long. Such as insulin, thyroxine, adrenalin (3) Synaptic signal (ne

5、urotransmitters) Secreted by neuronal cells. Reach another neuron by synaptic gap. Time of action is short. Such as Acetylcholine (Ach), noradrenaline(4) Gaseous signal Simple structure, half life is short and active in chemistry . Such as NO, CO.GAS MOLECULE (5) Autocrine signal Act back to their o

6、wn cells. Such as GF, cytokine, interferon, interleukin. 2. Intracellular molecule Ca2+ ions DG, ceramide lipid derivatives IP3 carbohydrate derivatives cAMP cGMP nucleotides Ras, JAK, Raf proteinsSecond messenger: Small molecules synthesized in cells in response to an external signal are the second

7、 messengers, which are responsible for intracellular signal transduction. Such as Ca2+, DG, Cer, IP3, cAMP, cGMPThird messengers: Third messengers are the molecules which transmit message from outside to inside of nucleous or from inside to outside of nucleous, also called DNA binding protein.Effect

8、 by membrane receptorsEffect by intracellular receptorsIntracellular moleculesExtracellular moleculesSignal moleculescAMP, cGMP, IP3, DG, Ca2+Proteins and peptides:Hormones, cytokinesAmino acid derivatives:Catecholamines Fatty acid derivatives:Prostaglandins Steroid hormones, Thyroxine, VD3 2 Recept

9、orReceptor Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules. Glycoprotein or Lipoproteinligand A small molecule that binds specifically to a larger one; for example, a

10、hormone is the ligand for its specific protein receptor. Membrane receptors membrane GlycoproteinIntracellular receptors Cytosol or nuclei DNA binding protein (1) Ligand-gate ion channels type (cyclic receptor) ligandreceptorion channel open or close1. membrane receptorsc is - a c t in g e le m e n

11、tn u c le u se x p r e s s io nc e ll m e m b e r a n ep h o s p h o r y la t io n o f e n z y m e s o r p r o te in se ffe c t sC a M -P KC a2 +-C a MC a2 +I P3D Gc A M Pc G M PP K AP K GP K CA T PG T PP I P2(P C )G A C G CG P Lp e p tid e h o r m o n e sn e u r o t r a n s m itte r sA F Pn e u r o

12、 t r a n s m itte r sh y p o t h a la m ic p itu itr inPtr a n s -a c tin g fa c t o r 1) 7-helices transmembrane receptor (2) G Protein-Coupled Receptors (serpentine R) CytosolicsideOligosaccharideunit G protein refers to any protein which binds to GDP or GTP and act as signal transduction. G prote

13、ins consist of three different subunits ( , , -subunit). -subunit carries GTPase activity, binding and hydrolysis of GTP.2) G protein (Guanylate binding protein) Gs sACcAMPGi iACcAMPGq q PI-PLCIP3+DAGGo oion channel Gt t cGMP PDEcGMP Rhodopsin3) Classes of G proteinc is-a c tin g e le m e n tn u c l

14、e u se x p r e ssio nc e ll m e m b e r a n ep h o sp h o r y la tio n o f e n z y m e s o r p r o te in se ffe c tsC a M -P KC a2 +-C a MC a2 +IP3D Gc A M Pc G M PP K AP K GP K CA T PG T PP IP2(P C )G A C G CG P Lp e p tid e h o r m o n e sn e u r o tr a n sm itte r sA F Pn e u r o tr a n sm itte r

15、 sh y p o th a la m ic p itu itr inPtr a n s-a c tin g fa c to rGlucagon -adrenaline s ACACTH -adrenalineangiotensin acetylcholine(M2 M4)GF release inhibitory factor iAC Ribosylation of Arg of G G s -ATPG s -ADPACcAMPCl- + H2OCavity of intestinediarrheaHCO3-Cholera toxinATPasePertussis toxin i -ADP-

16、ribosylationGi AC allergy of histaminecAMP AC cGMP PDE (phosphodiesterase） PLC PLA2 Channel protein4) Effect proteins of G protein cAMPATP 5) Pathway of G protein linked receptorHRG proteinEssecondary messegerProtein kinasePhophorylation of Es or functional proteinBiological effect (3) Single transm

17、embrane -helix receptor Tyrosine protein kinase Receptor (catalytic receptor) IGFR, EGFR Non tyrosine protein kinase Receptor Growth Hormone R, interferon RTyrosine protein kinase Receptoror receptor tyrosine kinase (RTK) Cys-richdomainImmunoglobulin-likedomainEGFRIGF-1RPDGFRFGFRIntracellularinsulin

18、 effectsCytosolInsulinNon-receptor tyrosine kinase (NRTK) Domain of Downstream molecules of TPKR SH2 domain (Scr homology 2 domain)SH3 domainPH domain (pleckstrin homology domain)Membrane receptor ANP Soluble receptor NO, CO(4) Guanylate cyclase (GC) receptor 2. Intracellular receptor (transcription

19、 regulated receptor) Intracellular R is trans-acting elememt cis-acting element gene expressionLocalized in the cytosol and/or in the nucleus. ligand: Steroid H, VD3, Thyroxine 3. Properties of binding of H and R highly specificity highly affinity saturation reversible binding special function model

20、 4. Control of receptor activity Phosphorylation or dephosphorylation of R Phospholipid of membrane Enzyme catalyzed hydrolysis G protein regulation(1) Recognize the special ligand(2) Binding to special ligand(3) Signal transduction biological effect5. Function of receptor 3 Pathway of Signal Transd

21、uction Signal transduction mediated by membrane receptor cAMP dependent-protein kinase A pathway cGMP dependent PKG pathway Ca2+ dependent PK pathway Tyrosine protein Kinase pathway NF-B pathway TGF- pathway1. cAMP dependent-protein kinase A pathway HRG proteinPhosphorylation of Es or functional pro

22、teinsBiological effectsPKAcAMPAC (1) cAMP metabolism Mg2+PPic A M PH2O5 -A M Phormons: glucagon, epinephrineinactive AC active ACATPcAMPinactive PKA active PKAphosphorylase b kinasephosphorylase b kinasePATPADPH2OPiphosphorylase bPPATPADPPiH2OATPADPglycogen synthaseglycogen synthasePH2OPi protein ph

23、osphatase-1(active)(inactive)inhibitor-1 (active)inhibitor-1 (inactive)phosphorylase aATPPPiACPDEAC： Adenylate cyclasePDE： PhosphodiesterasePDEH2ONNNNNH2OHOHOHCH2HHHOPOOOPOOOPOOOATPACPPiNNNNNH2OHOHOCH2HHHOPOOcAMPNNNNNH2OHOHOHCH2HHHOPOOO5-AMP (2) Mechanism of cAMP effect Activate cAMP-dependent prote

24、in kinase (PKA).(3) PKA effect Phosphorylate specifically Ser/Thr residues in several proteins（1）Regulation of metabolism（2）Regulation of gene expressionCRE : cAMP response element (TGACGTCA)CREB: CRE binding protein DNACRECREBPKATranscriptionmRNACREBPKACREBCREBCREBCREBCREBCREB2. Ca2+ dependent PK p

25、athway (1) Ca2+ -DAG -dependent PKC pathwayHRPIP2G proteinPLCIP3DG ERPKCCa2+PSBiological effectsPhosphorylation of Es or functional proteinsCa 2+i 0.01-1 mol/L（10-7 mol/L ）Ca 2+o 2.5mmol/L（10-3 mol/L ） 5000100001） Function of DG and IP3 IP3 + Ropen of Ca2 channel Ca2PS, Ca2DGPKC 2）Function of PKC re

26、gulation of metabolismPKC Ser/Thr-P of R, enzyme, Protein of Mb. Gene expression Late response:Trans-acting factor-PThird messengerImmediate early genesThird messenger-PActivate genesCell proliferationPKCPKCEarly response:(2) Ca2-CaM dependent protein kinase pathway HRG proteinPLCIP3Ca2+CaMCaMKBiolo

27、gical effectsPhosphorylation of Es or functional proteinsCalmodulin (CaM）：）： Ca2 binding protein 4 Ca2+ CaM Ca2- CaM CaM kinase Ser/Thr - P Ca2 pump, AC GC Es (glycogen synthase, phosphorylase kinase) 3. cGMP-dependent PKG pathway Biological effectsPhosphorylation of Es or functional proteinsANPNO,

28、COSoluble GCPKGcGMPReceptor-linked GC(1) cGMP (2) Function of PKG Ser/Thr- P of protein and EPPic A M P5 -A M Phormons: glucagon, epinephrineinactive AC active ACATPcAMPinactive PKA active PKAphosphorylase b kinasephosphorylase b kinasePATPADPH2OPiphosphorylase bPPATPADPPiH2OATPADPglycogen synthaseg

29、lycogen synthasePH2OPi protein phosphatase-1(active)(inactive)inhibitor-1 (active)inhibitor-1 (inactive)phosphorylase aATPPPi5 -G M P受 体 型 T P K细胞膜GCPDEGC: Guanylate cyclase ANP（atrial natriuretic peptides） GC NO cGMP PKG Vascular dilatation4. Tyrosine-protein kinase pathway (TPK) TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change. T