CHAPTER 15

1. CHAPTER 15 Cell Signaling and Signal Transduction: Communication Between Cells

2. Introduction • Cells must respond adequately to external stimuli to survive. • Cells respond to stimuli via cell signaling. • Some signal molecules enter cells; others bind to cell-surface receptors.

3. 15.1 The Basic Elements of Cell Signaling Systems (1) • Extracellular messenger molecules transmit messages between cells. • In autocrine signaling, the cell has receptors on its surface that respond to the messenger. • During paracrine signaling, messenger molecules travel short distances through extracellular space. • During endocrine signaling, messenger molecules reach their target cells through the bloodstream.

4. Types of intercelular signaling

5. The Basic Elements of Cell Signaling Systems (2) • Receptors on or in target cells receive the message. • Some cell surface receptors generate an intracellular second messenger through an enzyme called an effector. • Other surface receptors recruit proteins to their intracellular domains.

6. Overview of signaling pathways

7. The Basic Elements of Cell Signaling Systems (3) • Signaling pathways consist of a series of proteins. • Each protein in a pathway alters the conformation of the next protein. • Protein conformation is usually altered by phosphorylation. • Target proteins ultimately receive a message to alter cell activity. • This overall process is called signal transduction.

8. A signal transduction pathway

9. 15.2 A Survey of Extracellular Messengers and Their Receptors (1) • Extracellular messengers include: • Small molecules such as amino acids and their derivatives. • Gases such as NO and CO • Steroids • Eicosanoids, which are lipids derived from fatty acids. • Various peptides and proteins

10. A Survey of Extracellular Messengers and Their Receptors (2) • Receptor types include: • G-protein coupled receptors (GPCRs) • Receptor protein-tyrosine kinases (RTKs) • Ligand gated channels • Steroid hormone receptors • Specific receptors such as B-and T-cell receptors

11. 15.3 G Protein-Coupled Receptors and Their Second Messengers (1) • G protein-coupled receptors (GPCRs) are numerous. • GPCRs have seven transmembrane domains and interact with G proteins.

12. A GPCR and a G protein

13. A GPCR and a G protein

14. Examples of GPCRs and their ligands

15. G Protein-Coupled Receptors and Their Second Messengers (2) • Signal Transduction by G Protein-Coupled Receptors • Ligand binding on the extracellular domain changes the intracellular domain. • Affinity for G proteins increases, and the receptor binds a G protein intracellularly. • GDP is exchanged for GTP on the G protein, activating the G protein. • One ligand-bound receptor can activate many G proteins.

16. Mechanism of receptor-mediated activation/inhibition by G proteins

17. G Protein-Coupled Receptors and Their Second Messengers (3) • Termination of the Response • Desensitization – by blocking active receptors from turning on additional G proteins. • G protein-coupled receptor kinase (GRK) activates a GPCR via phosphorylation. • Proteins called arrestins compete with G proteins to bind GPCRs. • Termination of the response is accelerated by regulators of G protein signaling (RGSs).

18. G Protein-Coupled Receptors and Their Second Messengers (4) • Bacterial Toxins, such as cholera toxin and pertussis virulence factors, target GPCRs and G proteins. • Second Messengers • The Discovery of Cyclic AMP • It is a second messenger, which is released into the cytoplasm after binding of a ligand. • Second messengers amplify the response to a single extracellular ligand.

19. The localized formation of cAMP

20. G Protein-Coupled Receptors and Their Second Messengers (5) • Phosphatidylinositol-Derived Second Messengers • Some phospholipids of cell membranes are converted into second messengers by activated phospholipases. • Phosphatidylinositol Phosphorylation • Phosphoinositides (PI) are derivatives of phosphatodylinositol.

21. Phospholipid-based second messengers

22. G Protein-Coupled Receptors and Their Second Messengers (6) • Phosphatidylinositol-specific phospholipase C- produces second messengers derived from phosphatidylinositol-inositol triphosphate (IP3) and diacylglycerol (DAG). • DAG activates protein kinase C, which phosphorylates serine and threonine residues on target proteins. • The phosphorylated phosphoinositides form lipid-binding domains called PH domains.

23. The generation of second messengers as a result of breakdown of PI

24. G Protein-Coupled Receptors and Their Second Messengers (7) • One IP3 receptor is a calcium channel located at the surface of the smooth endoplasmic reticulum. • Binding of IP3 opens the channel and allows Ca2+ ions to diffuse out.

25. Examples of responses mediated by Protein Kinase C

26. Cellular responses elicited by adding IP3

27. G Protein-Coupled Receptors and Their Second Messengers (8) • Regulation of Blood Glucose Levels • Different stimuli acting on the same target cell may induce the same response. • Glucagon and epinephrine bind to different receptors on the same cell. • Both hormones stimulate glucoses breakdown and inhibit its synthesis. • cAMP is activated by the G protein of both hormone receptors • Responses are amplified by signal cascades.

28. The reactions that lead to glucosestorage or mobilization

29. G Protein-Coupled Receptors and Their Second Messengers (9) • Glucose Metabolism: An Example of a Reponse Induced by cAMP • cAMP is synthesized by adenylyl cyclase. • cAMP evokes a reaction cascade that leads to glucose mobilization. • Once formed, cAMP molecules diffuse into the cytoplasm where they bind a cAMP-dependent protein kinase (protein kinase A, PKA).

30. Formation of cAMP from ATP

31. The response by a liver cell to glucagonor epinephrine

32. G Protein-Coupled Receptors and Their Second Messengers (10) • Other Aspects of cAMP Signal Transduction Pathways • Some PKA molecules phosphorylate nuclear proteins. • Phosphorylated transcription factors regulate gene expression. • Phosphatases halt the reaction cascade. • cAMP is produced as long as the external stimulus is present.

33. The variety of processes that can be affected by changes in [cAMP]

34. Examples of hormone-induced responses mediated by cAMP

35. PKA-anchoring protein signaling

36. G Protein-Coupled Receptors and Their Second Messengers (11) • The Role of GPCRs in Sensory Perception • Rhodopsin is a photosensitive protein for black-and-white vision that is also a GPCR. • Several color receptors are GPCRs. • Odorant receptors in the nose are GPCRs. • Taste receptors for bitter and some sweet flavors are GPCRs.

37. The Human Perspective: Disorders Associated with G Protein-Coupled Receptors (1) • Several disorders are caused by defects in receptors or G proteins. • Loss of function mutations result in nonfunctional signal pathways. • Retinitis pigmentosa, a progressive degeneration of the retina, can be caused my mutations in rhodopsin’s ability to activate a G protein.

38. Transmembrane receptor responsible for causing human diseases

39. Human diseases linked to the G protein pathway

40. The Human Perspective: Disorders Associated with G Protein-Coupled Receptors (2) • Gain of function mutations may create a constitutively activated G protein. • Some benign thyroid tumors are caused by a mutation in a receptor. • Certain polymorphisms in G protein-related genes may result in an increased susceptibility to asthma or high blood pressure, as well as decreased susceptibility to HIV.

41. 15.4 Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (1) • Protein-tyrosine kinases phosphorylate tyrosine residues on target proteins. • Protein-tyrosine kinases regulate cell growth, division, differentiation, survival, and migration. • Receptor protein-tyrosine kinases (RTKs) are cell surface receptors of the protein-tyrosine kinase family.

42. Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (2) • Receptor Dimerization • Results from ligand binding. • Protein kinase activity is activated. • Tyrosine kinase phosphorylates another subunit of the receptor (autophosphorylation). • RTKs phosphorylate tyrosines within phosphotyrosine motifs.

43. Steps in the activation of RTK

44. Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (3) • Phosphotyrosine-Dependent Protein-Protein Interactions • Phosphorylated tyrosines bind effector proteins that have SH2 domains and PTB domains. • SH2 and PTB domain proteins include: • Adaptor proteins that bind other proteins. • Docking proteins that supply receptors with other tyrosine phosphorylation sites. • Signaling enzymes (kinases) that lead to changes in cell. • Transcription factors

45. The interaction between SH2 domain and a peptide contain a phosphotyrosine

46. A diversity of signaling proteins

47. Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (4) • The Ras-MAP Kinase Pathway • Ras is a G protein embedded in the membrane by a lipid group. • Ras is active when bound to GTP and inactive when bound to GDP.

48. The structure of a G protein and theG protein cycle

49. Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (5) • Ras-MAP kinase pathway (continued) • Accessory proteins play a role: • GTPase-activating proteins (GAPs) shorten the active time of Ras. • Guanine nucleotide-exchange factors (GEFs) stimulate the exchange of GDP for GTP. • Guanine nucleotide-dissociation inhibitors (GDIs) inhibit release of GDP.

50. Protein-Tyrosine Phosphorylation as a Mechanism for Signal Transduction (6) • Ras-MAP kinase pathway (continued) • The Ras-MAP kinase cascade is a cascade of enzymes resulting in activation of transcription factors. • Adapting the MAP kinase to transmit different types of information: • End result differs in different cells/situations. • Specificity of the MAP kinase response due to differences in the types of kinases participating and differences in spatial organization of components.