Chapter 9. Cellular Signaling

Transcription

1 Chapter 9 Cellular Signaling

2 Cellular Messaging Page 215 Cells can signal to each other and interpret the signals they receive from other cells and the environment Signals are most often chemicals The same small set of cell signaling mechanisms shows up in diverse species and processes

3 Evolution of Cell Signaling Page 215 The yeast Saccharomyces cerevisiae has two mating types, a and α Cells of different mating types locate each other via secreted factors specific to each type The binding of a mating factor at the cell surface initiates a series of steps called a signal transduction pathway Molecular details of signal transduction in yeasts and mammals are very similar.

4 Communication Between Mating Yeast Cells 1 2 Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. Mating. Binding of the factors to receptors induces changes in the cells that lead to their fusion. Receptor a Yeast cell, mating type a a a factor factor Yeast cell, mating type Page New a/ cell. The nucleus of the fused cell includes all the genes from the a and cells. a/ signal trnsduction pathway

5 Page 215 Ancestral signaling molecules likely evolved in prokaryotes and single-celled eukaryotes and were adopted for use in their multicellular descendants Cell signaling is critical among prokaryotes A concentration of signaling molecules allows bacteria to sense local population density in a process called quorum sensing

6 Communication among Bacteria Page Individual rodshaped cells 0.5 mm 2 Aggregation in process 3 Sporeforming structure (fruiting body) *quorum sensing *biofilm synchronously Fruiting bodies

7 Modes of Cell-Cell Signaling 1.Direct Cell-Cell Signaling Plasma membranes Page 217 Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions. Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes. (b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces.

8 2. Signaling by Secreted Molecules Page 217 (a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell, such as a muscle or nerve cell.

9 Page 217 (e.g. T lymphocytes)

10 Page (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones reach virtually all body cells, but are bound only by some cells.

11 The Three Stages of Cell Signaling Page 218

12 The Three Stages of Cell Signaling Page 218

13 The Three Stages of Cell Signaling Page 218 Signal transduction pathway

14 Animation: Overview of Cell Signaling

15 Ligand : hydrophilic compounds (water-soluble) Page 219 Cell- surface transmembrane receptors play crucial roles in the biological systems of animals.

16 Ligand : hydrophobic compounds Page 222 & 223 Hormone (aldosterone) EXTRACELLULAR FLUID 1 The steroid hormone aldosterone passes through the plasma membrane. Receptor protein Plasma membrane Hormonereceptor complex 2 Aldosterone binds to a receptor protein in the cytoplasm, activating it. mrna NUCLEUS CYTOPLASM DNA New protein 3 The hormonereceptor complex enters the nucleus and binds to specific genes. 4 The bound protein acts as a transcription factor, stimulating the transcription of the gene into mrna. 5 The mrna is translated into a specific protein.

17 Receptors in the Plasma Membrane Page 220 Most signal receptors are plasma membrane proteins G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane

18 Membrane Receptors: Page G protein-coupled receptors 2.Single-transmembrane segment (1-TMS) catalytic receptor (receptor tyrosine kinase) 3.Oligomeric ion channels (ion channel receptors) GTP or GDP

19 The Structure of G Protein-Coupled Receptors Page 220

20 G Protein-Coupled Receptors Signal-binding site Page 220 Segment that interacts with G proteins G-protein-linked receptor Plasma Membrane Activated receptor Signal molecule Inactive enzyme CYTOPLASM GDP G-protein (inactive) Enzyme GDP GTP Activated enzyme GTP GDP P i Cellular response

21 First messenger (signal molecule such as epinephrine) G protein Adenylyl cyclase Page 226 G-protein-linked receptor GTP ATP camp Second messenger Protein kinase A Cellular responses

22 Cyclic AMP(Second Messenger) Page 225

23 Page 220 trimeric G protein small G protein

24 Page 220

25 Page 220 G protein-coupled receptors (GPCRs) are cell surface transmembrane receptors that work with the help of a G protein G proteins bind the energy-rich GTP GPCRs are all very similar in structure GPCR systems are extremely widespread and diverse in their functions

26 Membrane Receptors: Page G protein-coupled receptors 2.Single-transmembrane segment (1-TMS) catalytic receptor (receptor tyrosine kinase) 3.Oligomeric ion channels (ion channel receptors)

27 Receptor Tyrosine Kinase Page 221 Ligand-binding domain Transmembrane domain cytosolic domain autophosphorylation

28 Page 221

29 Page 221 Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers

30 Membrane Receptors: Page G protein-coupled receptors 2.Single-transmembrane segment (1-TMS) catalytic receptor (receptor tyrosine kinase) 3.Oligomeric ion channels (ion channel receptors)

31 Ion Channel Receptors Page 222

32 Page 223 A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na or Ca 2, through a channel in the receptor

33 Intracellular Receptors Page Intracellular receptor proteins are found in the cytoplasm 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 hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

34 Ligand : hydrophobic compounds Page Hormone (aldosterone) EXTRACELLULAR FLUID 1 The steroid hormone aldosterone passes through the plasma membrane. Receptor protein Plasma membrane Hormonereceptor complex 2 Aldosterone binds to a receptor protein in the cytoplasm, activating it. mrna NUCLEUS CYTOPLASM DNA New protein 3 The hormonereceptor complex enters the nucleus and binds to specific genes. 4 The bound protein acts as a transcription factor, stimulating the transcription of the gene into mrna. 5 The mrna is translated into a specific protein.

35 Nitric oxide (a gas, small molecule) Page 222& 226 Stripped away (sildenafil) Viagra 威而鋼 phosphodiesterase GMP

36 Page 224 Signal Transduction Pathway: Cascades of Molecular Interactions Relay Signals from Receptors to Target Molecules in the Cell

37 A Phosphorylation Cascade Page 224 Signal molecule Receptor Activated relay molecule 1 A relay molecule activates protein kinase 1. Inactive protein kinase 1 Inactive protein kinase 2 5 Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. P i ATP Active protein kinase 1 PP ADP Inactive protein kinase 3 P i ATP Active protein kinase 2 PP ADP Inactive protein 2 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. P i P ATP PP Active protein kinase 3 3 Active protein kinase 2 then catalyzes the phosphorylation (and activation) of protein kinase 3. ADP P 4 Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell s response to the signal. Active protein P Cellular response protein kinase vs. protein phosphatase

38 Protein Phosphorylation and Dephosphorylation Page 224 Phosphorylation and dephosphorylation of proteins is a widespread cellular mechanism for regulating protein activity Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Many relay molecules in signal transduction pathways are protein kinases, creating a phosphorylation cascade

39 Page 225 Protein phosphatases rapidly 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

40 Small Molecules and Ions as Second Messengers Many signaling pathways involve second messengers Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by GPCRs and RTKs Cyclic AMP and calcium ions are common second messengers Page 225

41 Cyclic AMP Page 225

42 Cyclic AMP Page 225 Cyclic AMP (camp) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to camp in response to an extracellular signal

43 Page 226 PKA: protein kinase A (serine/threonine kinase) C:catalytic subunit R:regulatory subunit *CREB: camp response element binding protein

44 Page 227 vibrio cholerae 霍亂弧菌産生 cholera toxin modified G protein is unable to hydrolyze GTP to GDP (camp increase)

45 Endoplasmic reticulum (ER) ATP Plasma membrane Page 227 Mitochondrion Nucleus Ca 2+ pump CYTOSOL ATP EXTRACELLULAR FLUID High [Ca 2+ ] Low [Ca 2+ ]

46 Calcium Ions Page 226 Calcium ions (Ca 2 ) are used widely as a second messenger Ca 2 can function as a second messenger because its concentration in the cytosol is normally much lower than the concentration outside the cell A small change in number of calcium ions thus represents a relatively large percentage change in calcium concentration

47 Calcium and IP3 in Signaling Pathways Page 227 DAG:diacylglycerol

48 Calcium and IP3 in Signaling Pathways Page 227

49 Calcium and IP3 in Signaling Pathways Page 227

50 Page 228 Response: Cell signaling leads to regulation of transcription or cytoplasmic activities

51 Nuclear and Cytoplasmic Responses Page 228 Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or in the nucleus Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule in the signaling pathway may function as a transcription factor

52 Page 228 Other pathways regulate the activity of enzymes rather than their synthesis For example, a signal could cause opening or closing of an ion channel in the plasma membrane, or a change in cell metabolism

53 Nuclear Responses to a Signal: the Activation of a Specific Gene by a Growth factor Page 228 MAPK (Mitogen-activated protein kinase) pathway

54 Signal Amplification Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Page 229 Active adenylyl cyclase (10 2 ) Response Glycogen Glucose 1-phosphate (10 8 molecules) 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 )

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57 Signaling pathways can also affect the overall behavior of a cell; for example, a signal could lead to cell division

58 The Specificity of Cell Signaling and Coordination of the Response Page 230

59 The Specificity of Cell Signaling and Coordination of the Response Page 230

60 Page 230 Signal transduction usually involves multiple steps Multistep pathways can greatly amplify a signal Multistep pathways provide more opportunities for coordination and regulation of the cellular response

61 Signaling Efficiency: Scaffolding Proteins & Signaling Complexes Page 230

62 Yeast Page 230

63 Termination of the Signal: --GTPase Page phosphodiesterase --phosphatase

64 Regulation of the Response Page A response to a signal may not be simply on or off There are four aspects of signal regulation: Amplification of the signal (and thus the response) Specificity of the response Overall efficiency of response, enhanced by scaffolding proteins Termination of the signal

65 Apoptosis of a Human White Blood Cell Page 231

66 Apoptosis (Programmed Cell Death) Page 232

67 Necrosis Apoptosis Page 232

68 Apoptosis (Programmed Cell Death) Page 232

69 Molecular Basis of Apoptosis in C. elegans Page 232

70 Molecular Basis of Apoptosis in C. elegans Page 232 Caspase

71 1.Extrinsic apoptotic pathway (the Death Receptor Pathway) 2.Intrinsic apoptotic pathway (the Mitochondrial Pathway) Page FADD:Fas-Associated Protein with a Death Domain

72 Effect of Apoptosis during Paw Development in the Mouse Page 233

73 Apoptotic Pathways and the Signals That Trigger Them Page 232 In humans and other mammals, several different pathways, including about 15 caspases, can carry out apoptosis Apoptosis can be triggered by signals from outside the cell or inside it Internal signals can result from irreparable DNA damage or excessive protein misfolding

74 Page 233 Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals For example, apoptosis is a normal part of development of hands and feet in humans (and paws in other mammals) Apoptosis may be involved in some diseases (for example, Parkinson s and Alzheimer s); interference with apoptosis may contribute to some cancers.