Chapter 9 Cellular Signaling
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
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.
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 215 3 New a/ cell. The nucleus of the fused cell includes all the genes from the a and cells. a/ signal trnsduction pathway
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
Communication among Bacteria Page 215 1 Individual rodshaped cells 0.5 mm 2 Aggregation in process 3 Sporeforming structure (fruiting body) *quorum sensing *biofilm synchronously Fruiting bodies
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.
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.
Page 217 (e.g. T lymphocytes)
Page 217-218 (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.
The Three Stages of Cell Signaling Page 218
The Three Stages of Cell Signaling Page 218
The Three Stages of Cell Signaling Page 218 Signal transduction pathway
Animation: Overview of Cell Signaling
Ligand : hydrophilic compounds (water-soluble) Page 219 Cell- surface transmembrane receptors play crucial roles in the biological systems of animals.
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.
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
Membrane Receptors: Page 220-222 1.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
The Structure of G Protein-Coupled Receptors Page 220
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
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
Cyclic AMP(Second Messenger) Page 225
Page 220 trimeric G protein small G protein
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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
Membrane Receptors: Page 220-222 1.G protein-coupled receptors 2.Single-transmembrane segment (1-TMS) catalytic receptor (receptor tyrosine kinase) 3.Oligomeric ion channels (ion channel receptors)
Receptor Tyrosine Kinase Page 221 Ligand-binding domain Transmembrane domain cytosolic domain autophosphorylation
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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
Membrane Receptors: Page 220-222 1.G protein-coupled receptors 2.Single-transmembrane segment (1-TMS) catalytic receptor (receptor tyrosine kinase) 3.Oligomeric ion channels (ion channel receptors)
Ion Channel Receptors Page 222
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
Intracellular Receptors Page 222-223 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
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.
Nitric oxide (a gas, small molecule) Page 222& 226 Stripped away (sildenafil) Viagra 威而鋼 phosphodiesterase GMP
Page 224 Signal Transduction Pathway: Cascades of Molecular Interactions Relay Signals from Receptors to Target Molecules in the Cell
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
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
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
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
Cyclic AMP Page 225
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
Page 226 PKA: protein kinase A (serine/threonine kinase) C:catalytic subunit R:regulatory subunit *CREB: camp response element binding protein
Page 227 vibrio cholerae 霍亂弧菌産生 cholera toxin modified G protein is unable to hydrolyze GTP to GDP (camp increase)
Endoplasmic reticulum (ER) ATP Plasma membrane Page 227 Mitochondrion Nucleus Ca 2+ pump CYTOSOL ATP EXTRACELLULAR FLUID High [Ca 2+ ] Low [Ca 2+ ]
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
Calcium and IP3 in Signaling Pathways Page 227 DAG:diacylglycerol
Calcium and IP3 in Signaling Pathways Page 227
Calcium and IP3 in Signaling Pathways Page 227
Page 228 Response: Cell signaling leads to regulation of transcription or cytoplasmic activities
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
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
Nuclear Responses to a Signal: the Activation of a Specific Gene by a Growth factor Page 228 MAPK (Mitogen-activated protein kinase) pathway
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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Signaling pathways can also affect the overall behavior of a cell; for example, a signal could lead to cell division
The Specificity of Cell Signaling and Coordination of the Response Page 230
The Specificity of Cell Signaling and Coordination of the Response Page 230
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
Signaling Efficiency: Scaffolding Proteins & Signaling Complexes Page 230
Yeast Page 230
Termination of the Signal: --GTPase Page 231 --phosphodiesterase --phosphatase
Regulation of the Response Page 228-231 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
Apoptosis of a Human White Blood Cell Page 231
Apoptosis (Programmed Cell Death) Page 232
Necrosis Apoptosis Page 232
Apoptosis (Programmed Cell Death) Page 232
Molecular Basis of Apoptosis in C. elegans Page 232
Molecular Basis of Apoptosis in C. elegans Page 232 Caspase
1.Extrinsic apoptotic pathway (the Death Receptor Pathway) 2.Intrinsic apoptotic pathway (the Mitochondrial Pathway) Page 232-233 FADD:Fas-Associated Protein with a Death Domain
Effect of Apoptosis during Paw Development in the Mouse Page 233
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
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.