1. Chapter 15 Cellular Signal Transduction The biochemistry and molecular biology department of CMU

2. 2. Intracellular receptor (transcription regulated receptor) Intracellular R is trans-acting elememt cis-acting element gene expression Localized in the cytosol and/or in the nucleus. ligand: Steroid H, VD 3, Thyroxine

4. 3. Properties of binding of H and R highly specificity highly affinity saturation reversible binding special function model

5. 4. Control of receptor activity Phosphorylation or dephosphorylation of R Phospholipid of membrane Enzyme catalyzed hydrolysis G protein regulation

6. (1) Recognize the special ligand (2) Binding to special ligand (3) Signal transduction biological effect 5. Function of receptor

7. §3 Pathway of Signal Transduction

8. Signal transduction mediated by membrane receptor cAMP dependent-protein kinase A pathway cGMP dependent PKG pathway Ca 2+ dependent PK pathway Tyrosine protein Kinase pathway NF-κB pathway TGF- βpathway

9. 1. cAMP dependent-protein kinase A pathway HR G protein Phosphorylation of Es or functional proteins Biological effects PKA cAMPAC

10. (1) cAMP metabolism AC PDE AC ： Adenylate cyclase PDE ： Phosphodiesterase

12. (2) Mechanism of cAMP effect Activate cAMP-dependent protein kinase (PKA).

14. (3) PKA effect

16. Phosphorylate specifically Ser/Thr residues in several proteins （ 1 ） Regulation of metabolism （ 2 ） Regulation of gene expression

18. CRE : cAMP response element ( TGACGTCA ) CREB: CRE binding protein

19. DNA CRE CREB PKA Ｐ Transcription mRNA CREB PKA Ｐ CREB Ｐ Ｐ Ｐ Ｐ Ｐ Ｐ

21. 2. Ca 2+ dependent PK pathway (1) Ca 2+ -DAG -dependent PKC pathway H R PIP 2 G protein PLC IP 3 DG ER PKC Ca 2+ PS Biological effects Phosphorylation of Es or functional proteins

23. [Ca 2+ ] i 0.01-1  mol/L （ 10 -7 mol/L ） [Ca 2+ ] o 2.5mmol/L （ 10 -3 mol/L ） 5000~10000×

24. 1 ） Function of DG and IP 3 IP 3 + R→open of Ca 2 ＋ channel →[Ca 2 ＋ ]↑ PS, Ca 2 ＋ DGPKC ↑

26. 2 ） Function of PKC regulation of metabolism PKC →Ser/Thr-P of R, enzyme, Protein of Mb. Gene expression

27. Late response: Trans-acting factor-P Third messenger Immediate early genes Third messenger-P Activate genes Cell proliferation PKC Early response:

29. (2) Ca 2 ＋ -CaM dependent protein kinase pathway HR G protein PLC IP 3 Ca 2+ CaM CaMK Biological effects Phosphorylation of Es or functional proteins

30. Calmodulin (CaM ）： Ca 2 ＋ binding protein 4 Ca 2 ＋ + CaM → Ca 2 ＋ - CaM ↓ CaM kinase↑ ↓ Ser/Thr - P ↓ Ca 2 ＋ pump, AC ↑ GC ↑ Es (glycogen synthase, phosphorylase kinase)

33. 3. cGMP-dependent PKG pathway Biological effects Phosphorylation of Es or functional proteins ANP NO, CO Soluble GC PKG cGMP Receptor- linked GC

34. (1) cGMP (2) Function of PKG Ser/Thr- P of protein and E GC PDE GC: Guanylate cyclase

35. ANP （ atrial natriuretic peptides ） ↓ GC NO ↓ cGMP ↓ PKG ↓ Vascular dilatation

37. 4. Tyrosine-protein kinase pathway (TPK) TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change. TPK ： receptor TPK ： Mb. non receptor TPK ： cytosol

38. (1) Receptor TPK － Ras － MAPK pathway GRB 2, SOS, Ras, Raf Small G protein: Ras MAPK (mitogen-activated protein kinase) ： MAPK 、 MAPKK 、 MAPKKK

39. EGF, PDGF receptor TPK Ras － GTP SOS － P GRB 2 － P Raf － P MAPKK － P MAPK － P trans-acting factor expression nucleus －P－P

40. (2) JAKs － STAT pathway ligand non TPK receptor JAKs STAT gene expression

41. JAKs STAT: Signal transductors and activator of transcription

42. interferons inactive STAT Plasma membrane STAT complex Nuclear membrane gene Interferons response element transcription

45. Dimerization of Receptor Interferon Autophosphorylation of JAK Phosphorylation of STAT Nuclear translocation of STAT Interferon response element Expression of gene

46. 5. Nuclear factor-κB pathway

47. 6. TGF-βpathway

48. Intracellular receptor (DNA transcription regulated receptor) Steroid H, VD 3, Thyroxine Cytosolic R: glycocorticosteroid H Nuclear R: thyroxine, estrogen, androgen, progesterone

50. Serum binding protein With bound bormone