1. Last Class: A. Membrane Proteins and their functions 1. membrane proteins are mobile yet organized 2. carrier and channel proteins B. Signaling Transduction 1. Ligand Receptor Interactions, 2. Intracellular signaling molecules, 3. molecule switches: phosphorylation and GTP binding, 4. Signaling integration, 5. complex formation, 6. Signaling amplification, 7. Signaling desensitization

2. Cell Communication Different Receptor Types Ion channel-linked receptors *GPCR signaling *Enzyme linked receptors

3. G Protein Coupled Receptors (GPCR)

4. A G-Protein-Coupled Receptor Or G Protein-linked Receptor 7 transmembrane domains

5. The disassembly of G-Protein upon stimulation Spontaneous deactivation is very fast, in minutes. However, with the help of RGS (regulator of G protein signaling, a GAP for  unit), signals can be shut off even faster

6. The Activation cycle of G- Protein

7. GPCR Signaling Mechanism Movie

8. GPCR Signaling: cAMP

9. The visualization of cAMP in nerve cells GPCR->Gs->adenylyl cyclase->cAMP Gi

10. cAMP cycle: GPCR->Gs->adenylyl cyclase->cAMP Cyclic AMP phosphodiesterase breaks down cAMP to 5’-AMP

11. The function of cAMP Targeting PKA (cyclic-AMP-dependent protein kinase A)

12. The Whole Signaling Network related to cAMP

13. Terminology: CRE(cyclic AMP response element); CREB: CRE binding protein; CBP: CREB binding protein

14. Movie cAMP and PKA signaling pathway

15. GPCR Signaling: Calcium Movie: calcium signaling in Neuronal cells

16. Three Types of Inositol phospholipids PI, PI(4)P, PI(4,5)P2

17. Phospholipase C-  (PLC-  ) Produces DAG (diacylglycerol) and IP3 (inositol 1,4,5- trisphosphate (IP3)) Gq->PLC- 

18. Gq signaling pathways and Calcium

19. Fertilization of an egg by a sperm triggering an increase in cytosolic Calcium 3 major types of calcium channels: 1.Voltage dependent Ca channels on plasma membrane 2.IP3-gated Ca release channels on ER membrane 3.Ryanodine receptor on ER membrane

20. Calcium uptake and deprivation 1. Na/Ca exchanger on plasma membrane, 2. Ca pump on ER membrane, 3. Ca binding molecules, 4. Ca pump on Mitochondia

21. Calcium Frequency encoding signaling strength Local Ca blips, sparks, puffs, reflecting local opening of individual channels in ER, strong local signal induces global activity, the elevated Calcium trigger calcium deprivation system

22. Targeting molecules for Calcium Calcium binding protein Calmodulin

23. Ca 2+ /calmodulin dependent protein kinase (CaM-kinase) Memory function: 1. calmodulin dissociate after 10 sec of low calcium level; 2. remain active after calmodulin dissociation

24. Ca 2+ /calmodulin dependent protein kinase (CaM-kinase) Frequency decoder of Calcium oscillation High frequence, CaM-kinase does not return to basal level before the second wave of activation starts

26. Desensitization of GPCR 1. Inhibitory structural alteration of receptor; 2. receptor internalization; 3. receptor degration GRK (G protein-linked receptor kinase) Arrestin takes to clathrin-coated pits and degradation

27. GPCR Signaling Summary 1. G-protein types 2. cAMP and Calcium signaling pathways 3. desensitization

28. Enzyme-Linked Cell Surface Receptors *Receptor Tyrosine Kinase *Tyrosine kinase associated receptors *Receptor-like tyrosine phosphatase *Receptor serine/threonine kinase Receptor guanylyl cyclase Histidine like associated receptor

29. Receptor Tyrosine Kinases (RTKs)

30. Seven subfamilies of receptor tyrosine kinases

32. Three ways in which signaling proteins can cross-link receptor chains 1. dimer, 2. monomer but brought together by proteoglycan, 3. cluster on membrane

34. The importance of receptor oligomerization

35. The docking of signaling molecules at RTK

36. The binding of SH2-containing intracellular signaling proteins to an activated PDGF receptor

37. The structural view of SH2 domain

38. RTK Signaling: Ras Pathway

39. The regulation of Ras activity, a famous downstream molecule of RTK responsible for cancer development

40. The activation of Ras by RTK signaling

41. The MAP-kinase regulated by Ras

42. RTK Signaling: PI3K Pathway

43. The inositol phospholipids generated by PI3K

44. The recruitment of signaling molecules with PH domains to the plasma membrane during B cell activation One PI3K pathway PH domain: pleckstrin homology domain

45. Movie: PI3K pathway regulating calcium and PKC

46. Another PI3K pathway to regulate cell survival

47. Another PI3K pathway to regulate cell migration PI3K->PIP3->GEF->Rac->Wave->Arp2/3->Actin polymerization Movie: chemotaxis, PI3K and cell migration

48. Intracellular Signaling Pathways activated by RTKs and GPCRs

49. 1.Tyrosine kinase associated receptors Integrins: cell-extracellular matrix adhesion Binding to Src and FAK

50. 1.Receptorlike tyrosine phosphatases Intracellular protein and receptor

51. 1.Receptor Serine/threonine kinase 2.Transforming growth factor (TGF-b) and Smad signaling pathway

53. 1.Protein kinase Summary

54. Enzyme-linked Receptor Signaling Summary 1. receptor types 2. RTK and its signaling: Ras and PI3K 3. Tyrosine kinase associated receptors and Receptor-like tyrosine phosphatase 4. Receptor serine/threonine kinase, TGF-  and Smad

55. Other Signaling Pathways Proteolysis mediated

56. 1.Notch and Delta interaction Lateral inhibition

57. 1.The inhibitory pathway of Notch Proteolysis-mediated

58. 1.The inhibitory pathway of Notch Proteolysis-mediated

59. 1.Wnt Signaling pathway LRP: LDL-receptor-related protein; GSK-3  : glycogen synthase kinase-3  APC: adenomatous polyposis coli;

60. 1.NF-KB pathway

61. Summary 1. GPCR signaling: PKA and Calcium 2. Enzyme-linked Receptor signaling: RTK- >Ras and PI3K 3. Proteolysis-mediated signaling pathways