Ch26 Cell Signalling

1. Ch26 Cell Signalling Yuki Juan NTU May 19, 2003

2. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

3. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

4. Term Definition • Second messengers: • A small intracellular regulatory molecules which causes cell responses. • E. g. Cyclic AMP

5. Outline of Receptor-mediated Signalling receptor Target cell

6. Cellular Responses to Singals

7. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

8. What Are The Singalling Molecules • Neurotransmitters • Endocrine Howmones: (Table 26.1) • The “classical” singalling molecules • Growth factors and cytokines • Regarded as singals • Which may induce cell growth and division or inhibit it • May affect differentiation • Instruct the cell to undergo apoptosis • Vitamins A and D derivatives • Retinoic acid (Vit A): singalling molecule in embryonic development and normal cell growth • Vitamin D3: control of genes involved in calcium absorption from the intestine

9. How Hormone Binding To Surface Receptor

10. Growth Factors and Cytokines • Most cytokines/growth factors are paracrine, some are autocrine • The first known growth factor was platelet-derived growth factor (PDGF) • PDGF stimulates cell division and repair • Epidermal growth factor (EGF) • stimulates the growth of Skin cells • Colony stimulating factors (CSFs) • Stimulate the growth of colonies of white cells on the culture plates.

11. Autocrine Singals and Paracrine Signals • Autocrine signals affect the cell producing them. • Paracrine singals diffuse only a short distance to affect nearby cells

12. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

13. The Structures of the Lipid-soluble signalling Molecules • They can combine with their specific receptors which exist inside the cell rather than in the membrane

14. Gene Activation by Steroid Hormones • The glucocorticoid receptor: one of a superfamily of steroid/thyroxine receptors • Binding to DNA sites by zinc fingers

15. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

16. Central Principle of Control by Many Extracellular Signals • Key processes in cell signalling are protein phosphorylation by protein kinases and reversal by protein phosphatases

17. Tyrosine Phosphorylation by Tyrosine Kinase

18. Tyrosine Kinase Type of Receptors and The Other Type of Signalling Adaptor molecules

19. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

20. Tyrosine Kinase-associated Receptors • Ras signal transduction pathway • Ras : a protein exits in all eukaryotic cells • There are no small molecular weight second messengers in this pathway—all of the components are proteins • Ras was discovered as the oncogenic protein coded for by the rat sarcoma virus • Phosphatidylinositide 3-kinase pathway • JAK/STAT protein-associated receptor

21. Raf, MEK and ERK: mitogen-activated protein kinases (MAP) kinases Raf: rat sarcoma; MAPKKK MEK: Map kinase/ERK; MAPKK ERK: extracellular siganl-regulated protien kinase; MAPK The Ras Singal Transduction Pathway

22. The Ras Singal Transduction Pathway

23. The Control of The Ras Protein

24. A Rapid Molecular Switch Mechanism

25. Multiple Signal Pathways Of The Ras Type

26. Phosphatidylinositide 3-kinase Pathway • PI 3 kinase involved in • Cell proliferation • Differentiation • Other cellular activities including metabolic control • Insulin

27. Simplified Insulin Singalling Pathway IRS: insulin receptor substrate PKB: protein kinase B

28. Production of The Second Messenger

29. JAK/STAT Protein-associated Receptor • Interferons • A protective proteins released by cells infected by virus • STAT proteins • Singal transducer and activator of transcription • SH2 domains bind to the phosphorylated receptors • JAK kinase: • Janus kinase • Has two catalytic sites

30. The Singalling Pathway by Which g-interferon Activates Specific Gene Transcription

31. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

32. The G-protein-coupled Receptors • G protein: • Heterotrimeric • A protein made up of three different subunits: a, b, g • G protein receptor have no enzymic activity

33. The Structure of The b2-adrenergic Recptor

34. cAMP

35. The Control of Adenylate Cyclase Activity by a Hormone Such As Epinephrine

36. The b2-adrenergic Recptor Function • PKA: protein kinase A • CREB: cAMP response element binding protein • CRE: cAMP response element of gene promoter

37. Hydrolysis of Phosphatidylinositol-4, 5-bisphosphate

38. The Phosphatidylinositol Cascade

39. Phorbol Esters Tumor-promoting effect

40. Structure of a Rod Cell

41. The Structures of Light Singal Molecules

42. The G-protein-coupled Receptor Involved In Vision

43. Simplified Diagram of The Visual Process

44. Outline • Introduction • What are the singalling molecules • Intracellular receptor-mediated responses • Membrane receptor-mediated singalling systems • Tyrosine kinase-associated receptors • The G-protein-coupled receptors • Singal transduction pathway using cGMP as second messenger

45. Formation of 3’,5’–cyclic GMP

46. Production of The Second Messenger cGMP by Two Routes

47. Simplified Summary Diagram of The Singal Transduction Pathways

48. Ch28 Virus and Viroids Yuki Juan

49. Virus • Much smaller • It generates no energy and catalyses no reactions • Structure simple • Genetic materials: DNA or RNA • Protein • 病毒的區分 • 依外觀區分 • 依遺傳物質區分

50. How Are Virus Get Into Cells ? • The receptor-mediated endocytosis