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  • 图 16-3 含 TPK 结 构 域 的 受 体

Third messanger Third messanger Presentation Transcript

  • Chapter 15Cellular Signal Transduction The biochemistry and molecular biology department of CMU
  • When environment changes: Monad——responds directly. Multicellular organisms——signalthrough elaborate system ofintercellular or intracellularcommunication , and consequentlyregulate functions of organisms.
  • Signaling moleculeReceptor of target cell Signal transductionIntracellular molecule biological effect
  • §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 cellular responses.
  • • 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 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 signal (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 their own 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 proteins
  • Second messenger: Small molecules synthesized in cellsin response to an external signal arethe second messengers, which areresponsible for intracellular signaltransduction. Such as Ca2+, DG, Cer, IP3, cAMP,cGMP
  • Third messengers: Third messengers are the moleculeswhich transmit message from outsideto inside of nucleous or from inside tooutside of nucleous, also called DNAbinding protein.
  • Proteins and peptides: Effect by Hormones, cytokines membrane Amino acid derivatives: receptors Catecholamines Extracellular Fatty acid derivatives: molecules Prostaglandins Effect by Signal intracellular Steroid hormones,molecules Thyroxine, VD3 receptors Intracellular cAMP, cGMP, IP3, DG, Ca2+ molecules
  • §2 Receptor
  • Receptor Receptors are specific membraneproteins, which are able to recognizeand bind to corresponding ligandmolecules, become activated, andtransduce signal to next signalingmolecules. Glycoprotein or Lipoprotein
  • ligand   A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor.
  • • Membrane receptors membrane Glycoprotein• Intracellular receptors Cytosol or nuclei DNA binding protein
  • 1. membrane receptors(1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open orclose
  • (2) G Protein-Coupled Receptors (serpentine R)1) 7-helices transmembranereceptor
  • Oligosaccharide unitCytosolic side
  • 2) G protein (Guanylate binding protein)• G protein refers to any protein whichbinds to GDP or GTP and act as signaltransduction.• G proteins consist of three differentsubunits (α, β, γ -subunit).• α -subunit carries GTPase activity,binding and hydrolysis of GTP.
  • 3) Classes of G protein Gs→ α s→AC→cAMP↑  Gi→ α i→AC→cAMP↓  Gq→ α q →PI-PLC→IP3+DAG  Go→ α o→ion channel Gt→ α t →cGMP PDE→cGMP→ Rhodopsin
  • Glucagonβ-adrenaline →α s →AC↑ACTHα-adrenalineangiotensin Ⅱ →α i→AC↓acetylcholine(M2 M4)GF release inhibitory factor
  •  
  • Cholera toxinRibosylation of Arg of Gα ATPaseG α s -ATP Gα s -ADP ACcAMP Cl- + H2O Cavity of intestine HCO3- diarrhea
  • Pertussis toxinα i -ADP-ribosylation Gi AC↑ cAMP ↑allergy of histamine
  • 4) Effect proteins of G protein AC cGMP PDE (phosphodiesterase ) PLC PLA2 Channel protein
  • cAMPATP
  • 5) Pathway of G protein linked receptor H R G protein Es secondary messeger Protein kinasePhophorylation of Es or functional protein Biological effect
  • (3) Single transmembrane α-helix receptor• Tyrosine protein kinase Receptor (catalytic receptor) IGF - R, EGF - R• Non tyrosine protein kinase Receptor Growth Hormone R, interferon R
  • Tyrosine protein kinase Receptor or receptor tyrosine kinase (RTK) Cys-rich domain Immunoglobulin -like domainEGFR IGF-1R PDGFR FGFR
  • Insulin IntracellularCytosol insulin effects
  • Non-receptor tyrosine kinase (NRTK)
  • Domain of Downstream molecules of TPKRSH2 domain (Scr homology 2 domain)SH3 domainPH domain (pleckstrin homology domain)
  • (4) Guanylate cyclase (GC) receptorMembrane receptor –ANPSoluble receptor – NO, CO
  • 2. Intracellular receptor (transcription regulated receptor) Intracellular R is trans-actingelememt cis-acting elementgene expression Localized in the cytosol and/or inthe nucleus. ligand: Steroid H, VD3, Thyroxine
  • 3. Properties of binding of H and R• highly specificity• highly affinity• saturation• reversible binding• special function model
  • 4. Control of receptor activity• Phosphorylation or dephosphorylation of R• Phospholipid of membrane• Enzyme catalyzed hydrolysis• G protein regulation
  • 5. Function of receptor(1) Recognize the special ligand(2) Binding to special ligand(3) Signal transduction biological effect
  • §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-κB pathway  • TGF- βpathway
  • 1. cAMP dependent-protein kinase A pathway H R G protein AC cAMP PKAPhosphorylation of Es or functional proteins Biological effects
  • (1) cAMP metabolism AC PDEATP 2+ cAMP 2+ 5-AMP Mg Mg PPi H2OPDE : PhosphodiesteraseAC : Adenylate cyclase
  • NH2 N N O O O N NO P O P O P O CH2 O ATP O O O H H H H OH OH PPi AC NH2 NH2 N N N N N N O N N PDE O CH2 O O P O CH2 O 5-AMP cAMP H H H2O O H H H H H H O P O OH OH OH O
  • (2) Mechanism of cAMP effect Activate cAMP-dependentprotein kinase (PKA).
  • (3) PKA effect
  • Phosphorylate specifically Ser/Thr residues in severalproteins ( 1 ) Regulation ofmetabolism ( 2 ) Regulation of geneexpression
  • hormons: glucagon, epinephrine active AC inactive AC ATP phosphorylase b kinase PiATP cAMPinactive PKA active PKA P ADP phosphorylase b kinase H2O ATP ADP ATP ADP P Pglycogen glycogensynthase phosphorylase b phosphorylase a synthase(active) (inactive) Pi H2O Pi H2O protein phosphatase-1 inhibitor-1 inhibitor-1 P (inactive) ATP (active)
  • CRE : cAMP response element (TGACGTCA)CREB: CRE binding protein
  • CRE DNA Transcription mRNA CREB CREB CR CR CRE EB EB CRCREB PP B CREB P EB P P P PKA PKA P P
  • 2. Ca2+ dependent PK pathway (1) Ca2+ -DAG -dependent PKC pathway PIP2H R G protein PLC IP3 DG ER Ca2+ PS PKC Phosphorylation of Es or functional proteins Biological effects
  • [Ca 2+]i 0.01-1 µmol/L ( 10-7 mol/L )[Ca 2+]o 2.5mmol/L ( 10-3 mol/L )5000~10000×
  • 1 ) Function of DG and IP3 IP3 + R→open of Ca2 +channel →[Ca2 + ]↑ DG PKC ↑ PS, Ca2 +
  • 2 ) Function of PKC• regulation of metabolism PKC →Ser/Thr-P of R, enzyme, Protein of Mb.• Gene expression  
  • Early response: PKC Trans-acting factor-PImmediate early genes Third messenger Late response: PKC Third messenger-P Activate genes Cell proliferation
  • (2) Ca2 + -CaM dependent proteinkinase pathwayH R G protein PLC IP3 Ca2+ CaM CaMK Phosphorylation of Es or functional proteins Biological effects
  • Calmodulin (CaM ): Ca2 + binding protein 4 Ca2 + + CaM → Ca2 + - CaM ↓ CaM kinase↑ ↓   Ser/Thr-P ↓ Ca2 + pump, AC ↑ GC ↑Es (glycogen synthase, phosphorylasekinase)
  • 3. cGMP-dependent PKG pathway ANP NO, CO Receptor- linked GC cGMP Soluble GC PKGPhosphorylation of Es or functional proteins Biological effects
  • (1) cGMP GC PDEGTP 2+ cGMP 2+ 5-GMP Mg Mg PPi H2O GC: Guanylate cyclase (2) Function of PKG Ser/Thr- P of protein and E
  • ANP ( atrial natriureticpeptides ) ↓ GC NO ↓ cGMP ↓ PKG ↓Vascular dilatation
  • peptide hormones neurotransmittersneurotransmitters AFP hypothalamic pituitrin G AC GC G PL cell memberane ATP GTP PIP2(PC) cAMP cGMP IP3 DG Ca2+ Ca2+-CaM PKA PKG PKC CaM-PK phosphorylation of enzymes or proteins effects trans-acting factor P cis-acting element nucleus expression
  • 4. Tyrosine-protein kinase pathway (TPK)• TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change.• TPK : receptor TPK : Mb. non receptor TPK : cytosol
  • (1) Receptor TPK - Ras - MAPK pathway• GRB2, SOS, Ras, Raf• Small G protein: Ras• MAPK (mitogen-activated protein kinase) : MAPK 、 MAPKK 、 MAPKKK
  • EGF, PDGF GRB2 - P ϸreceptor TPK ÊÜ ÐÍTPK Ìå Ras - GTP °û SOS - P Ĥ Raf - P MAPKK - P nucleus trans-acting factor - P MAPK - P expression
  • (2) JAKs - STAT pathway ligand non TPK receptor JAKs STAT gene expression
  • • JAKs• STAT: Signal transductors and activator of transcription
  • interferons Plasma membrane ÖÊĤ JAK P£- £- P 84 P 113 STAT complex 113 91 P 91 84 P 48inactive STAT Nuclear membrane ºËĤ P 113 P 91 84 P transcription 48 gene »ùÒò Interferons response element ¸ÉÈÅ Ó¦´ð Ôª¼þ ËØ
  • Interferon Dimerization of ReceptorAutophosphorylation of JAK Phosphorylation of STATNuclear translocation of STAT Interferon response element Expression of gene
  • 5. Nuclear factor-κB pathway
  • 6. TGF-βpathway
  • Intracellular receptor (DNA transcription regulated receptor)• Steroid H, VD3, Thyroxine• Cytosolic R: glycocorticosteroid H• Nuclear R: thyroxine, estrogen, androgen, progesterone
  • Serum binding proteinWith bound bormone