1、,Chapter 15Cellular Signal Transduction,The biochemistry and molecular biology department of CMU,When environment changes:,Monadresponds directly.Multicellular organismssignal through elaborate system of intercellular or intracellular communication，and consequently regulate functions of organisms.,S
2、ignaling molecule,Receptor of target cell,Intracellular molecule,biological effect,Signal transduction,1 Signaling Molecules,Signaling molecules,Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellula
3、r responses.,Extracellular molecules Intracellular molecules,1. Extracellular molecules,protein & peptides: Hormone, cytokine AA & its derivatives: Gly, Glu, adrenaline, thyroxine Steroid: Sex Hormone, glucocorticosteroid Fatty acid derivatives: prostaglandin,(1) Paracrine signaling (local chemical
4、mediators),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 sign
5、al (neurotransmitters),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
6、 their own cells. Such as GF, cytokine, interferon, interleukin.,2. Intracellular molecule,Ca2+ ions DG, ceramide lipid derivatives IP3 carbohydratederivatives cAMP cGMP nucleotides Ras, JAK, Raf proteins,Second messenger:,Small molecules synthesized in cells in response to an external signal are th
7、e second messengers, which are responsible for intracellular signal transduction.Such as Ca2+, DG, Cer, IP3, cAMP, cGMP,Third 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 protei
8、n.,Effect by membrane receptors,Effect by intracellular receptors,Intracellular molecules,Extracellular molecules,Signal molecules,cAMP, cGMP, IP3, DG, Ca2+,Proteins and peptides:,Hormones, cytokines,Amino acid derivatives:,Catecholamines,Fatty acid derivatives:,Prostaglandins,Steroid hormones, Thyr
9、oxine, VD3,2 Receptor,Receptor,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 Lipoprotein,ligand A small molecule that binds specifically to a larger
10、 one; for example, a hormone is the ligand for its specific protein receptor.,Membrane receptors membrane Glycoprotein Intracellular receptorsCytosol or nuclei DNA binding protein,(1) Ligand-gate ion channels type (cyclic receptor)ligandreceptorion channel open or close,1. membrane receptors,1) 7-he
11、lices transmembrane receptor,(2) G Protein-Coupled Receptors (serpentine R),G protein refers to any protein which binds to GDP or GTP and act as signal transduction.G proteins consist of three different subunits (, , -subunit). -subunit carries GTPase activity, binding and hydrolysis of GTP.,2) G pr
12、otein (Guanylate binding protein),Gs sACcAMPGi iACcAMPGq q PI-PLCIP3+DAGGo oion channelGt t cGMP PDEcGMPRhodopsin,3) Classes of G protein,Glucagon -adrenaline s AC ACTH -adrenaline angiotensin acetylcholine(M2 M4) GF release inhibitory factor,iAC,Ribosylation of Arg of G,G s -ATP,Gs -ADP,AC,cAMP,Cl-
13、 + H2O,Cavity of intestine diarrhea,HCO3-,Cholera toxin,ATPase,Pertussis toxin i -ADP-ribosylation Gi ACallergy of histamine,cAMP,ACcGMP PDE (phosphodiesterase）PLC PLA2Channel protein,4) Effect proteins of G protein,cAMP,ATP,5) Pathway of G protein linked receptor,H,R,G protein,Es,secondary messeger
14、,Protein kinase,Phophorylation of Es or functional protein,Biological effect,(3) Single transmembrane -helix receptor,Tyrosine protein kinase Receptor (catalytic receptor) IGFR, EGFRNon tyrosine protein kinase ReceptorGrowth Hormone R, interferon R,Tyrosine protein kinase Receptor or receptor tyrosi
15、ne kinase (RTK),Intracellular insulin effects,Cytosol,Insulin,Non-receptor tyrosine kinase(NRTK),Domain of Downstream molecules of TPKR,SH2 domain (Scr homology 2 domain) SH3 domain PH domain (pleckstrin homology domain),Membrane receptor ANP Soluble receptor NO, CO,(4) Guanylate cyclase (GC) recept
16、or,2. Intracellular receptor (transcription 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 affinitysaturation
17、reversible binding special function model,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 effect,5. Fu
18、nction of receptor,3 Pathway of Signal Transduction,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- pathway,1. cAMP dependent-protein kinase A pathway,H,R,
19、G protein,Phosphorylation of Es or functional proteins,Biological effects,PKA,cAMP,AC,(1) cAMP metabolism,AC,PDE,AC： Adenylate cyclase,PDE： Phosphodiesterase,(2) Mechanism of cAMP effect,Activate cAMP-dependent protein kinase (PKA).,(3) PKA effect,Phosphorylate specifically Ser/Thr residues in sever
20、al proteins（1）Regulation of metabolism（2）Regulation of gene expression,CRE : cAMP response element (TGACGTCA) CREB: CRE binding protein,DNA,CREB,PKA,Transcription,mRNA,CREB,PKA,2. Ca2+ dependent PK pathway,(1) Ca2+ -DAG -dependent PKC pathway,H,R,PIP2,G protein,PLC,IP3,DG,ER,PKC,Ca2+,PS,Biological e
21、ffects,Phosphorylation of Es or functional proteins,Ca 2+i 0.01-1 mol/L（10-7 mol/L ） Ca 2+o 2.5mmol/L（10-3 mol/L ） 500010000,1） Function of DG and IP3,IP3 + Ropen of Ca2 channel Ca2,PS, Ca2,DG,PKC ,2）Function of PKC,regulation of metabolismPKC Ser/Thr-P of R, enzyme,Protein of Mb. Gene expression,La
22、te response:,Trans-acting factor-P,Third messenger,Immediate early genes,Third messenger-P,Activate genes,Cell proliferation,PKC,PKC,Early response:,(2) Ca2-CaM dependent protein kinase pathway,H,R,G protein,PLC,IP3,Ca2+,CaM,CaMK,Biological effects,Phosphorylation of Es or functional proteins,Calmod
23、ulin (CaM）：,Ca2 binding protein 4 Ca2+ CaM Ca2- CaM CaM kinaseSer/Thr - PCa2 pump, AC GC Es (glycogen synthase, phosphorylase kinase),3. cGMP-dependent PKG pathway,Biological effects,Phosphorylation of Es or functional proteins,ANP,NO, CO,Soluble GC,PKG,cGMP,Receptor- linked GC,(1) cGMP,(2) Function
24、 of PKGSer/Thr- P of protein and E,GC,PDE,GC: Guanylate cyclase,ANP（atrial natriuretic peptides）GC NOcGMP PKG Vascular dilatation,4. Tyrosine-protein kinase pathway (TPK),TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change. TPK：receptor TPK：Mb.non receptor T
25、PK：cytosol,(1) Receptor TPKRasMAPK pathway,GRB2, SOS, Ras, Raf Small G protein: Ras MAPK (mitogen-activated protein kinase)：MAPK、MAPKK、MAPKKK,EGF, PDGF,receptor TPK,RasGTP,SOSP,GRB2P,(2) JAKsSTAT pathway,ligand,non TPK receptor,JAKs,STAT,gene expression,JAKs STAT: Signal transductors and activator o
26、f transcription,interferons,inactive STAT,Plasma membrane,STAT complex,Nuclear membrane,gene,Interferons response element,transcription,Dimerization of Receptor,Interferon,Autophosphorylation of JAK,Phosphorylation of STAT,Nuclear translocation of STAT,Interferon response element,Expression of gene,5. Nuclear factor-B pathway,6. TGF-pathway,Intracellular receptor (DNA transcription regulated receptor),Steroid H, VD3, Thyroxine Cytosolic R: glycocorticosteroid H Nuclear R: thyroxine, estrogen, androgen, progesterone,Serum binding protein With bound bormone,
