1. What’s happeningWhat’s happening?

2. Symphony of communication

3. LECTURE PRESENTATIONS For CAMPBELL BIOLOGY, NINTH EDITION Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson © 2011 Pearson Education, Inc. Lectures by Erin Barley Kathleen Fitzpatrick Cell Communication Chapter 11

4. Overview: Cellular Messaging Cell-to-cell communication is essential for both multicellular and unicellular organisms Biologists have discovered some universal mechanisms of cellular regulation Cells most often communicate with each other via chemical signals For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine © 2011 Pearson Education, Inc.

5. Cellular communication Types of signaling Contact Local ParacrineSynaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity

6. Cellular communication Types of signaling Contact Local ParacrineSynaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity

7. Cellular communication Types of signaling Contact Local ParacrineSynaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity

8. Cellular communication Types of signaling Contact Local ParacrineSynaptic Long-distance Endocrine system: via hormones Neuronal: via electricity

9. Figure 11.1

10. Concept 11.1: External signals are converted to responses within the cell Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cellConcept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities Concept 11.5: Apoptosis integrates multiple cell-signaling pathways

11. Concept 11.1: External signals are converted to responses within the cell Microbes provide a glimpse of the role of cell signaling in the evolution of life © 2011 Pearson Education, Inc.

12. Evolution of Cell Signaling The yeast, Saccharomyces cerevisiae, has two mating types, a and  Cells of different mating types locate each other via secreted factors specific to each type A signal transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response Signal transduction pathways convert signals on a cell’s surface into cellular responses © 2011 Pearson Education, Inc.

13. Communicati on between mating yeast cells How can this be analogized to people? Exchange of mating factors Receptor  factor a factor Yeast cell, mating type a Yeast cell, mating type  Mating New a/  cell 1 2 3 a a a/   

14. How could we find out how long ago cell communication evolved? © 2011 Pearson Education, Inc.

15. How could we find out how long ago cell communication evolved? See if similar mechanisms are present in bacteria and recently developed organisms like people. © 2011 Pearson Education, Inc.

16. Individual rod-shaped cells Spore-forming structure (fruiting body) Aggregation in progress Fruiting bodies 1 2 3 0.5 mm 2.5 mm The concentration of signaling molecules allows bacteria to sense local population density

17. Local and Long-Distance Signaling Cells in a multicellular organism communicate by chemical messengers –Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate by direct contact, or cell-cell recognition © 2011 Pearson Education, Inc.

18. Figure 11.4 Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions (b) Cell-cell recognition

19. Figure 11.5a Local signaling Target cell Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid. (a) Paracrine signaling using local regulators (b) Synaptic signaling with neurotransmitters Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Target cell is stimulated.

20. Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling

21. The Three Stages of Cell Signaling: 1.Reception 2.Transduction 3.Response © 2011 Pearson Education, Inc.

22. Animation: Overview of Cell Signaling Right-click slide / select “Play”

23. Figure 11.6-1 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM Reception Receptor Signaling molecule 1

24. Figure 11.6-2 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM ReceptionTransduction Receptor Signaling molecule Relay molecules in a signal transduction pathway 2 1

25. Figure 11.6-3 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM ReceptionTransduction Response Receptor Signaling molecule Activation of cellular response Relay molecules in a signal transduction pathway 3 2 1

26. Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape © 2011 Pearson Education, Inc.

27. Receptors in the Plasma Membrane There are three main types of membrane receptors 1.G protein-coupled receptors 2.Receptor tyrosine kinases 3.Ion channel receptors © 2011 Pearson Education, Inc.

28. G protein-coupled receptors (GPCRs) are the largest family of cell- surface receptors The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive G protein-coupled receptor Signaling molecule binding site Segment that interacts with G proteins

29. Figure 11.7b G protein-coupled receptor 21 3 4 Plasma membrane G protein (inactive) CYTOPLASM Enzyme Activated receptor Signaling molecule Inactive enzyme Activated enzyme Cellular response GDP GTP GDP GTP P i GDP Note: the enzyme is activated by shape change

30. Figure 11.8: The sturcutre of a G Protien-Coupled Receptor Plasma membrane Cholesterol  2 -adrenergic receptors Molecule resembling ligand

31. 2. Receptor tyrosine kinase Signaling molecule (ligand) 2 1 34 Ligand-binding site  helix in the membrane Tyrosines CYTOPLASM Receptor tyrosine kinase proteins (inactive monomers) Signaling molecule Dimer Tyr P P P P P P P P P P P P Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Activated relay proteins Cellular response 1 Cellular response 2 Inactive relay proteins 6 ATP 6 ADP

32. Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines –Benefit: A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Tidbit: Abnormal functioning of RTKs is associated with many types of cancers © 2011 Pearson Education, Inc.

33. Figure 11.7d Signaling molecule (ligand) 2 1 3 Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate open Cellular response Gate closed A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a ligand binds to the receptor, the gate allows specific ions, such as Na + or Ca 2+, through a channel in the receptor

34. Intracellular Receptors Intracellular receptor proteins are found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors –Examples of hydrophobic messengers are the steroid and thyroid (lipid soluble) hormones of animals © 2011 Pearson Education, Inc.

35. Figure 11.9-1 Hormone (testosterone) Receptor protein Plasma membrane DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID

36. Figure 11.9-2 Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID

37. Figure 11.9-3 Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID

38. Figure 11.9-4 Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID

39. Figure 11.9-5 Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein

40. Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Signal transduction usually involves multiple steps –What are some benefits of a multistep pathway a.k.a. cascade? © 2011 Pearson Education, Inc.

41. Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Signal transduction usually involves multiple steps, a.k.a. cascade? –Benefit 1: can amplify a signal: (A few molecules can produce a large cellular response) –Benefit 2: provide more opportunities for coordination and regulation of the cellular response © 2011 Pearson Education, Inc.

42. Protein Phosphorylation and Dephosphorylation is the cascade’s signal Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required © 2011 Pearson Education, Inc.

43. Receptor Signaling molecule Activated relay molecule Phosphorylation cascade Inactive protein kinase 1 Active protein kinase 1 Active protein kinase 2 Active protein kinase 3 Inactive protein kinase 2 Inactive protein kinase 3 Inactive protein Active protein Cellular response ATP ADP ATP ADP ATP ADP PP P P P P i Figure 11.10 “upstream”/”downstream” regulation

44. Small Molecules and Ions as Second Messengers The extracellular signal molecule (ligand) that binds to the receptor is a pathway’s “first messenger” Second messengers are small, nonprotein, water- soluble molecules or ions that spread throughout a cell by diffusion –Cyclic AMP and calcium ions are common second messengers © 2011 Pearson Education, Inc.

45. Figure 11.11 Adenylyl cyclase Phosphodiesterase Pyrophosphate AMP H2OH2O ATP P i P cAMP What other organic molecule do cAMP resemble? Why?

46. Figure 11.12 G protein First messenger (signaling molecule such as epinephrine) G protein-coupled receptor Adenylyl cyclase Second messenger Cellular responses Protein kinase A GTP ATP cAMP

47. Calcium Ions and Inositol Triphosphate (IP 3 ) Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration © 2011 Pearson Education, Inc.

48. Figure 11.13 Mitochondrion EXTRACELLULAR FLUID Plasma membrane Ca 2  pump Nucleus CYTOSOL Ca 2  pump Endoplasmic reticulum (ER) ATP Low [Ca 2  ] High [Ca 2  ] Key

49. © 2011 Pearson Education, Inc. Animation: Signal Transduction Pathways Right-click slide / select “Play”

50. G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2  GTP Figure 11.14-1: Calcium and IP 3 in signaling pathways

51. Figure 11.14-2 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2  (second messenger) Ca 2  GTP

52. Figure 11.14-3 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Cellular responses Ca 2  (second messenger) Ca 2  GTP

53. Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities The final activated molecule in the signaling pathway may have a response in the cytoplasm (e.g. changing shape of cytoskeleton or regulating enzymes) or function as a transcription factor © 2011 Pearson Education, Inc.

54. Figure 11.15 Growth factor Receptor Reception Transduction CYTOPLASM Response Inactive transcription factor Active transcription factor DNA NUCLEUS mRNA Gene Phosphorylation cascade P

55. Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Active protein kinase A (10 4 ) Inactive phosphorylase kinase Active phosphorylase kinase (10 5 ) Inactive glycogen phosphorylase Active glycogen phosphorylase (10 6 ) Glycogen Glucose 1-phosphate (10 8 molecules)

56. Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape © 2011 Pearson Education, Inc.

57. Wild type yeast (with shmoos)  Fus3  formin Mating factor activates receptor. Mating factor G protein-coupled receptor Shmoo projection forming Formin G protein binds GTP and becomes activated. 2 1 3 4 5 P P P P Formin Fus3 GDP GTP Phosphory- lation cascade Microfilament Actin subunit Phosphorylation cascade activates Fus3, which moves to plasma membrane. Fus3 phos- phorylates formin, activating it. Formin initiates growth of microfilaments that form the shmoo projections. RESULTS CONCLUSION What is this showing?

58. Figure 11.17a Wild type (with shmoos)

59. Fine-Tuning of the Response There are four aspects of fine-tuning to consider: 1.Amplification of the signal (and thus the response) 2.Specificity of the response 3.Overall efficiency of response, enhanced by scaffolding proteins 4.Termination of the signal © 2011 Pearson Education, Inc.

60. Signal Amplification Enzyme cascades amplify the cell’s response At each step, the number of activated products is much greater than in the preceding step © 2011 Pearson Education, Inc.

61. Figure 11.18 The specificity of cell signaling. Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Response 2Response 3 Response 4 Response 5 Activation or inhibition Cell B. Pathway branches, leading to two responses. Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

62. Figure 11.19 Signaling molecule Receptor Plasma membrane Scaffolding protein Three different protein kinases Signaling Efficiency: Scaffolding Proteins and Signaling Complexes

63. Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling If ligand concentration falls, fewer receptors will be bound Unbound receptors revert to an inactive state © 2011 Pearson Education, Inc.

64. Concept 11.5: Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide WHY IS THIS FUNCTION CRITICAL? © 2011 Pearson Education, Inc.

65. Concept 11.5: Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells © 2011 Pearson Education, Inc.

66. Figure 11.20: white blood cell apoptosis 2  m

67. Apoptosis in the Soil Worm Caenorhabditis elegans Apoptosis is important in shaping an organism during embryonic development The role of apoptosis in embryonic development was studied in Caenorhabditis elegans In C. elegans, apoptosis results when proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis © 2011 Pearson Education, Inc.

68. Figure 11.21 Mitochondrion Ced-9 protein (active) inhibits Ced-4 activity Receptor for death- signaling molecule Ced-4 Ced-3 Inactive proteins (a) No death signal Death- signaling molecule Ced-9 (inactive) Cell forms blebs Active Ced-4 Active Ced-3 Other proteases Nucleases Activation cascade (b) Death signal

69. Apoptotic Pathways and the Signals That Trigger Them Caspases are the main proteases (what are these?) that carry out apoptosis Apoptosis can be triggered by –An extracellular death-signaling ligand –DNA damage in the nucleus –Protein misfolding in the endoplasmic reticulum © 2011 Pearson Education, Inc.

70. Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers © 2011 Pearson Education, Inc.

71. Figure 11.22: apoptosis in paw development of the mouse Interdigital tissue Cells undergoing apoptosis Space between digits 1 mm

72. REVIEW Reception 1 2 3 TransductionResponse Receptor Signaling molecule Relay molecules Activation of cellular response