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What’s happening? Symphony of communication 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 Chapter 11 Cell Communication Lectures by Erin Barley Kathleen Fitzpatrick © 2011 Pearson Education, Inc. 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. Cellular communication Contact Types of signaling Local Paracrine Synaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity Cellular communication Contact Types of signaling Local Paracrine Synaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity Cellular communication Contact Types of signaling Local Paracrine Synaptic Long-distance Endocrine system: via hormones Neuronal: via elctricity Cellular communication Contact Types of signaling Local Paracrine Synaptic Long-distance Endocrine system: via hormones Neuronal: via electricity Figure 11.1 • 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 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. 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. factor Receptor Communicati on between mating yeast cells How can this be analogized to people? 1 Exchange of mating factors a a factor Yeast cell, Yeast cell, mating type a mating type 2 Mating a 3 New a/ cell a/ • How could we find out how long ago cell communication evolved? © 2011 Pearson Education, Inc. • 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. The concentration of signaling molecules allows bacteria to sense local population density 1 Individual rod-shaped cells 2 Aggregation in progress 0.5 mm 3 Spore-forming structure (fruiting body) 2.5 mm Fruiting bodies 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. Figure 11.4 Plasma membranes Gap junctions between animal cells (a) Cell junctions (b) Cell-cell recognition Plasmodesmata between plant cells Figure 11.5a Local signaling Target cell Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid. (a) Paracrine signaling using local regulators Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Target cell is stimulated. (b) Synaptic signaling with neurotransmitters Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling The Three Stages of Cell Signaling: 1. Reception 2. Transduction 3. Response © 2011 Pearson Education, Inc. Animation: Overview of Cell Signaling Right-click slide / select “Play” © 2011 Pearson Education, Inc. Figure 11.6-1 EXTRACELLULAR FLUID 1 Reception Receptor Signaling molecule CYTOPLASM Plasma membrane Figure 11.6-2 EXTRACELLULAR FLUID 1 Reception CYTOPLASM Plasma membrane 2 Transduction Receptor Relay molecules in a signal transduction pathway Signaling molecule Figure 11.6-3 EXTRACELLULAR FLUID 1 Reception CYTOPLASM Plasma membrane 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signaling molecule Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape © 2011 Pearson Education, Inc. 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. • G protein-coupled receptors (GPCRs) are the largest family of cellsurface receptors The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive Signaling molecule binding site Segment that interacts with G proteins G protein-coupled receptor Figure 11.7b Note: the enzyme is activated by shape change G protein-coupled receptor Plasma membrane Activated receptor 1 Inactive enzyme GTP GDP GDP CYTOPLASM Signaling molecule Enzyme G protein (inactive) 2 GDP GTP Activated enzyme GTP GDP Pi 3 Cellular response 4 Figure 11.8: The sturcutre of a G Protien-Coupled Receptor 2-adrenergic receptors Plasma membrane Cholesterol Molecule resembling ligand 2. Receptor tyrosine kinase Signaling molecule (ligand) Ligand-binding site helix in the membrane Signaling molecule Tyrosines CYTOPLASM Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) 1 Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Dimer 2 Activated relay proteins 3 Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P 6 ATP Activated tyrosine kinase regions (unphosphorylated dimer) 6 ADP Fully activated receptor tyrosine kinase (phosphorylated dimer) 4 Inactive relay proteins Cellular response 1 Cellular response 2 • 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. Figure 11.7d 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 Ca2+, through a channel in the receptor 1 Signaling molecule (ligand) 3 2 Gate closed Ions Plasma Ligand-gated membrane ion channel receptor Gate closed Gate open Cellular response 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. Figure 11.9-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA NUCLEUS CYTOPLASM Figure 11.9-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex DNA NUCLEUS CYTOPLASM Figure 11.9-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex DNA NUCLEUS CYTOPLASM Figure 11.9-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex DNA mRNA NUCLEUS CYTOPLASM Figure 11.9-5 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormonereceptor complex DNA mRNA NUCLEUS CYTOPLASM New protein 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. 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. 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. Figure 11.10 Signaling molecule Receptor “upstream”/”downstream” regulation Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP P Active protein kinase 2 PP Pi Inactive protein kinase 3 ATP ADP Pi Active protein kinase 3 PP Inactive protein P ATP P ADP PP Pi Active protein Cellular response 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, watersoluble molecules or ions that spread throughout a cell by diffusion – Cyclic AMP and calcium ions are common second messengers © 2011 Pearson Education, Inc. Figure 11.11 What other organic molecule do cAMP resemble? Adenylyl cyclase Phosphodiesterase H2O Pyrophosphate P Pi ATP cAMP Why? AMP Figure 11.12 First messenger (signaling molecule such as epinephrine) Adenylyl cyclase G protein G protein-coupled receptor GTP ATP cAMP Second messenger Protein kinase A Cellular responses Calcium Ions and Inositol Triphosphate (IP3) • Calcium ions (Ca2+) act as a second messenger in many pathways • Calcium is an important second messenger because cells can regulate its concentration © 2011 Pearson Education, Inc. Figure 11.13 EXTRACELLULAR FLUID Plasma membrane Ca2 pump Mitochondrion ATP Nucleus CYTOSOL Ca2 pump ATP Key High [Ca2 ] Ca2 pump Endoplasmic reticulum (ER) Low [Ca2 ] Animation: Signal Transduction Pathways Right-click slide / select “Play” © 2011 Pearson Education, Inc. Figure 11.14-1: Calcium and IP3 in signaling pathways EXTRACELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca2 Figure 11.14-2 EXTRACELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca2 Ca2 (second messenger) Figure 11.14-3 EXTRACELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor Phospholipase C PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Ca2 Ca2 (second messenger) Cellular responses 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. Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor P Response DNA Gene NUCLEUS mRNA Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose 1-phosphate (108 molecules) • Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape © 2011 Pearson Education, Inc. RESULTS What is this showing? formin Wild type yeast (with shmoos) Fus3 CONCLUSION 1 Mating factor activates receptor. Mating factor G protein-coupled Shmoo projection forming receptor Formin P Fus3 GDP GTP 2 G protein binds GTP and becomes activated. Fus3 Actin subunit P Phosphorylation cascade Fus3 Formin Formin P 4 Fus3 phosphorylates formin, activating it. P 3 Phosphorylation cascade activates Fus3, which moves to plasma membrane. Microfilament 5 Formin initiates growth of microfilaments that form the shmoo projections. Figure 11.17a Wild type (with shmoos) 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. 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. Figure 11.18 The specificity of cell signaling. Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Activation or inhibition Response 2 Response 3 Cell B. Pathway branches, leading to two responses. Response 4 Cell C. Cross-talk occurs between two pathways. Response 5 Cell D. Different receptor leads to a different response. Figure 11.19 Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Signaling molecule Plasma membrane Receptor Three different protein kinases Scaffolding protein 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. 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. 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. Figure 11.20: white blood cell apoptosis 2 m 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. Figure 11.21 Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-9 (inactive) Deathsignaling molecule Active Active Ced-4 Ced-3 Receptor for deathsignaling molecule Ced-4 Ced-3 Activation cascade Inactive proteins (a) No death signal Cell forms blebs (b) Death signal Other proteases Nucleases 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. • 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. Figure 11.22: apoptosis in paw development of the mouse Interdigital tissue Cells undergoing apoptosis Space between 1 mm digits REVIEW 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules Signaling molecule