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.
Figure 11.1 What are some physiological functions that are part of the fight-or-flight response?
Concept 11.1: External signals are converted to responses within the cell Biologists have discovered some universal mechanisms of cellular regulation Microbes (microorganisms) provide a glimpse of the role of cell signaling in the evolution of life 2011 Pearson Education, Inc.
Concept 11.1: External signals are converted to responses within the cell 1. The external signal released 2. How does the cell respond to the signal
Evolution of Cell Signaling Sex for example The yeast, Saccharomyces cerevisiae, have 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 Signals Cellular responses 2011 Pearson Education, Inc.
Figure 11.2 Receptor factor 1 Exchange of mating factors a Yeast cell, mating type a a factor Yeast cell, mating type 2 Mating Binding of the factors to the receptors induces changes that lead to their fusion a 3 New a/ cell The nucleus of the fused cell includes all the genes from the a and the ɑ cells a/
Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling molecules allows bacteria to sense local population density quorum sensing Allows bacterial populations to coordinate their behaviors so they can carry out activities that are only productive when performed by a given number of cells in synchrony. Biofilm aggregation of bacterial cells adhered to a surface. Examples?? 2011 Pearson Education, Inc.
Local and Long-Distance Signaling Cells in a multicellular organism communicate by chemical messengers Animal and plant cells have cell junctions (pores) 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 animal cells plant cells (a) Cell junctions (b) Cell-cell recognition
In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal 2011 Pearson Education, Inc.
Figure 11.5 Local signaling Long-distance signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Endocrine cell Blood vessel Secreting cell Secretory vesicle Neurotransmitter diffuses across synapse. Hormone travels in bloodstream. Local regulator diffuses through extracellular fluid. (a) Paracrine signaling Target cell is stimulated. (b) Synaptic signaling Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling
The Three Stages of Cell Signaling: A Preview Earl W. Sutherland discovered how the hormone epinephrine (adrenaline) acts on cells Stimulates the breakdown of glycogen in liver/muscle cells produces products that can be used in glycolysis for energy production. Or it can be dephosphorylated and released from the liver cell into the blood as glucose, which fuels cells throughout the body Mobilization of fuel reserve, which can be used by the animal to defend itself (fight) or escape from whatever elicited the scare (flight) 2011 Pearson Education, Inc.
The Three Stages of Cell Signaling: A Preview Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response 2011 Pearson Education, Inc.
2011 Pearson Education, Inc. Animation: Overview of Cell Signaling Right-click slide / select Play
Figure 11.6-1 EXTRACELLULAR FLUID Plasma membrane CYTOPLASM 1 Reception Receptor Signaling molecule
Figure 11.6-2 EXTRACELLULAR FLUID Plasma membrane CYTOPLASM 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Signaling molecule
Figure 11.6-3 EXTRACELLULAR FLUID Plasma membrane CYTOPLASM 1 Reception 2 Transduction 3 Response Receptor Relay molecules in a signal transduction pathway Activation of cellular response Signaling molecule
Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape The binding between a signal molecule (ligand) and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins 2011 Pearson Education, Inc.
Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane There are three main types of membrane receptors G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors 2011 Pearson Education, Inc.
G-protein-coupled receptor (GPCRs) are the largest family of cell-surface receptors A GPCR is a plasma membrane receptor that works with the help of a G protein The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive 2011 Pearson Education, Inc.
Figure 11.7a Signaling molecule binding site Segment that interacts with G proteins G protein-coupled receptor
Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme CYTOPLASM 1 GDP G protein (inactive) Enzyme 2 GDP GTP GDP GTP Activated enzyme GTP GDP P i 3 Cellular response 4 1. The g protein functions as a molecular switch that is either on or off depending on which of the two guanine nucleotides are attached [GTP (tri phosphate) or GDP (di phosphate)]. GDP bound= G protein is inactive (shown above) GTP bound= G protein is active
Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme CYTOPLASM 1 GDP G protein (inactive) Enzyme 2 GDP GTP GDP GTP Activated enzyme GTP GDP P i 3 Cellular response 4 2. The receptor and G proteins work with other proteins (usually enzymes). When a specific signaling molecule binds to the receptor on the extracellular side, the receptor is activated and changes shape. Its cytoplasmic side then binds to an inactive G protein, causing a GTP to replace GDP. This activates the G protein.
Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme CYTOPLASM 1 GDP G protein (inactive) Enzyme 2 GDP GTP GDP GTP Activated enzyme GTP GDP P i 3 Cellular response 4 3. The activated g protein leaves the receptor, then binds to an enzyme. The binding changes the enzymes shape and activity. Once activated, the enzyme can trigger the next stop leading to a cellular response.
Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme CYTOPLASM 1 GDP G protein (inactive) Enzyme 2 GDP GTP GDP GTP Activated enzyme GTP GDP P i 3 Cellular response 4 4. The changes in the enzyme and G protein are only temporary because the G protein also functions as an enzyme. It can change GTP to GDP. Now it is inactive again, the G protein leaves the enzyme, which returns to original state. The G protein is available for reuse.
Figure 11.8 2 -adrenergic receptors Molecule resembling ligand Plasma membrane Cholesterol β 2 -adrenergic agonists, are a class of drugs that act on the beta 2 -adrenergic receptor cause smooth muscle relaxation, resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders.
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 2011 Pearson Education, Inc.
Signaling molecule (ligand) helix in the membrane Ligand-binding site Signaling molecule osines CYTOPLASM Receptor tyrosine 1 kinase proteins (inactive monomers) 2 Activated relay proteins Dimer 6 ATP 6 ADP P P P P P P Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase 3 dimer) 4 (phosphorylated dimer) P P P P P P Inactive relay proteins Cellular response 1 Cellular response 2 1.Before the signaling molecule binds, the are individual units called monomers. Have an extracellular binding site. helix spanning the membrane Intracellular tail with many tyrosines
Signaling molecule (ligand) helix in the membrane Ligand-binding site Signaling molecule osines CYTOPLASM Receptor tyrosine 1 kinase proteins (inactive monomers) 2 Activated relay proteins Dimer 6 ATP 6 ADP P P P P P P Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase 3 dimer) 4 (phosphorylated dimer) P P P P P P Inactive relay proteins Cellular response 1 Cellular response 2 2. The binding of a signaling molecules causes 2 monomers to come together to form a dimer.
Signaling molecule (ligand) helix in the membrane Ligand-binding site Signaling molecule osines CYTOPLASM Receptor tyrosine 1 kinase proteins (inactive monomers) 2 Activated relay proteins Dimer 6 ATP 6 ADP P P P P P P Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase 3 dimer) 4 (phosphorylated dimer) P P P P P P Inactive relay proteins Cellular response 1 Cellular response 2 3. Dimerization activates the tyrosine kinase region of each monomer Each tyrosine kinase adds a phosphate from an ATP molecule to a tyrosine on the tail of the mother monomer.
Signaling molecule (ligand) helix in the membrane Ligand-binding site Signaling molecule osines CYTOPLASM Receptor tyrosine 1 kinase proteins (inactive monomers) 2 Activated relay proteins Dimer 6 ATP 6 ADP P P P P P P Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase 3 dimer) 4 (phosphorylated dimer) P P P P P P Inactive relay proteins Cellular response 1 Cellular response 2 4. Now that the receptor is fully activated, it is recognized by specific relay proteins inside the cell. Each such protein binds to a specific phosphorylated tyrosine undergoing a shape change that activates the bound protein. Each activated protein triggers a transduction pathway leading to a cellular response.
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 2011 Pearson Education, Inc.
Figure 11.7d 1 2 3 Signaling molecule (ligand) Gate closed Ions Gate open Gate closed Ligand-gated ion channel receptor Plasma membrane 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 hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes 2011 Pearson Education, Inc.
Figure 11.9-1 Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane DNA NUCLEUS CYTOPLASM
Figure 11.9-2 Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormonereceptor complex DNA NUCLEUS CYTOPLASM
Figure 11.9-3 Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormonereceptor complex DNA NUCLEUS CYTOPLASM
Figure 11.9-4 Hormone (testosterone) Receptor protein mrna EXTRACELLULAR FLUID DNA Plasma membrane Hormonereceptor complex The hormonereceptor complex enters the nucleus and binds to specific genes. NUCLEUS CYTOPLASM
Figure 11.9-5 Hormone (testosterone) Receptor protein EXTRACELLULAR FLUID Plasma membrane Hormonereceptor complex The bound protein acts as a transcription factor, stimulating the transcription of the gene into RNA protein mrna DNA NUCLEUS New protein CYTOPLASM
Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Signal transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation of the cellular response 2011 Pearson Education, Inc.
Signal Transduction Pathways The molecules that relay a signal from receptor to response are mostly proteins Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a shape change in a protein SHAPE DICTATES FUNCTION!!!! 2011 Pearson Education, Inc.
Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations (adding Phosphate groups P Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation 2011 Pearson Education, Inc.
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 Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of kinase 2, thus activating this second kinase. Inactive protein kinase 2 P i ATP PP ADP Active protein kinase 2 P PP=phosphatases Inactive protein kinase 3 P i ATP PP ADP Active protein kinase 3 P Finally, active protein kinase 3 phosphorylates a protein (pink) that brins about the cell s response to the signal. Inactive protein P i ATP PP ADP Active protein P 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 Second messengers participate in pathways initiated by GPCRs and RTKs Cyclic AMP and calcium ions are common second messengers 2011 Pearson Education, Inc.
Cyclic AMP 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 2011 Pearson Education, Inc.
Many signal molecules trigger formation of camp Other components of camp pathways are G proteins, G protein-coupled receptors, and protein kinases camp usually activates protein kinase A, which phosphorylates various other proteins Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase 2011 Pearson Education, Inc.
Figure 11.12 First messenger (signaling molecule such as epinephrine) G protein Adenylyl cyclase G protein-coupled receptor GTP G protein is activated (GTP bound) ATP camp Second messenger Adenylyl cyclase converts ATP to camp camp usually activates protein kinase A, which phosphorylates various other proteins cellular response Protein kinase A Cellular responses
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.
EXTRACELLULAR FLUID Plasma membrane Key CYTOSOL ATP ATP High [Ca 2 ] Ca 2 pump Mitochondrion Nucleus Ca 2 pump Low [Ca 2 ] Ca 2 pump Endoplasmic reticulum (ER) The calcium concentration in the cytosol is usually much lower than the extracellular side and ER. Protein pumps in the plasma membrane and the ER (driven by ATP) move calcium from the cytosol into the extracellular fluid and into the inside of the ER. Mitochondrial pumps, driven by chemiosmosis, move calcium into the mitochondria when the calcium level in the cytosol rises significantly.
A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol Pathways leading to the release of calcium involve inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as additional second messengers 2011 Pearson Education, Inc.
2011 Pearson Education, Inc. Animation: Signal Transduction Pathways Right-click slide / select Play
Figure 11.14-1 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein G protein-coupled receptor GTP IP 3 -gated calcium channel Phospholipase C PIP 2 DAG IP 3 (second messenger) 1. A signaling molecule binds to a receptor, leading to activation of phospholipase C (PLC) 2. PLC cuts PIP2 into DAG and IP3. Endoplasmic reticulum (ER) Ca 2 CYTOSOL
Figure 11.14-2 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein G protein-coupled receptor GTP Phospholipase C PIP 2 DAG IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2 Ca 2 (second messenger) 3. DAG functions as a second messenger. 4. IP3 binds to IP3 receptor (calcium channel) in the ER causing it to open. 5. Calcium flows out of the ER, raising the calcium level in the cytosol.
Figure 11.14-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein G protein-coupled receptor GTP Phospholipase C PIP 2 DAG IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2 Ca 2 (second messenger) Various proteins activated Cellular responses 6. The calcium ions activate the next protein in one or more signaling pathways.
Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities The cell s response to an extracellular signal is sometimes called the output response What is the nature of the final step in a signaling pathway? 2011 Pearson Education, Inc.
Nuclear and Cytoplasmic Responses 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 2011 Pearson Education, Inc.
Figure 11.15 Growth factor Receptor Reception Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor DNA Active transcription factor P Response Gene NUCLEUS mrna
Other pathways regulate the activity of enzymes rather than their synthesis 2011 Pearson Education, Inc.
Figure 11.16 Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction 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 ) Response Glycogen Glucose 1-phosphate (10 8 molecules)
Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape 2011 Pearson Education, Inc.
Figure 11.17 RESULTS CONCLUSION 1 Mating factor activates receptor. Wild type (with shmoos) Fus3 formin Mating factor G protein-coupled receptor Shmoo projection forming P Formin GDP 2 G protein binds GTP and becomes activated. 3 GTP Fus3 Phosphorylation cascade Fus3 P Phosphorylation cascade activates Fus3, which moves to plasma membrane. P Fus3 Formin Formin P 4 Fus3 phosphorylates formin, Microfilament activating it. 5 Actin subunit Formin initiates growth of microfilaments that form the shmoo projections.
Fine-Tuning of the Response There are four aspects of fine-tuning to consider Amplifying the signal (and thus the response) Specificity of the response Overall efficiency of response, enhanced by scaffolding proteins 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.
The Specificity of Cell Signaling and Coordination of the Response Different kinds of cells have different collections of proteins These different proteins allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different proteins and pathways Pathway branching and cross-talk further help the cell coordinate incoming signals 2011 Pearson Education, Inc.
Figure 11.18 Signaling molecule Receptor Relay molecules Activation or inhibition Response 1 Response 2 Response 3 Response 4 Response 5 Cell A. Pathway leads to a single response. 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.
Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Scaffolding proteins are large relay proteins to which other relay proteins are attached Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway In some cases, scaffolding proteins may also help activate some of the relay proteins 2011 Pearson Education, Inc.
Figure 11.19 Signaling molecule Plasma membrane Receptor Scaffolding protein Three different protein kinases
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 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 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 Deathsignaling molecule Ced-9 (inactive) Cell forms blebs Active Ced-4 Active Ced-3 Other proteases Receptor for deathsignaling molecule Ced-4 Ced-3 Inactive proteins Activation cascade Nucleases (a) No death signal (b) Death signal
Apoptotic Pathways and the Signals That Trigger Them Caspases are the main proteases (enzymes that cut up proteins) 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 evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson s and Alzheimer s); interference with apoptosis may contribute to some cancers Why??? 2011 Pearson Education, Inc.
Figure 11.22 Interdigital tissue Cells undergoing apoptosis 1 mm Space between digits