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
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
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
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
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
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 Ï¸receptor TPK ÊÜ ÐÍTPK Ìå Ras － GTP °û SOS － P Ä¤ 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 ÖÊÄ¤ JAK P£- £- P 84 P 113 STAT complex 113 91 P 91 84 P 48inactive STAT Nuclear membrane ºËÄ¤ 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