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Chapter 11 Cell Communication

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 Long-distance Paracrine Synaptic Neuronal: via elctricity Endocrine system: via hormones

Cellular communication Contact Types of signaling Local Long-distance Paracrine Synaptic Neuronal: via elctricity Endocrine system: via hormones

Cellular communication Contact Types of signaling Local Long-distance Paracrine Synaptic Neuronal: via elctricity Endocrine system: via hormones

Cellular communication Contact Types of signaling Local Long-distance Paracrine Synaptic Neuronal: via electricity Endocrine system: via hormones

Figure 11.1 Figure 11.1 How does cell signaling trigger the desperate flight of this gazelle?

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.

Yeast cell, mating type a Yeast cell, mating type   factor Receptor 1 Exchange of mating factors Communication between mating yeast cells How can this be analogized to people? a  a factor Yeast cell, mating type a Yeast cell, mating type  2 Mating a  Figure 11.2 Communication between mating yeast cells. 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 Figure 11.3 Communication among bacteria. 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.

Gap junctions between animal cells Plasmodesmata between plant cells DIRECT SIGNALING Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions Figure 11.4 Communication by direct contact between cells. (b) Cell-cell recognition

Neurotransmitter diffuses across synapse. Secreting cell Figure 11.5a Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Secreting cell Secretory vesicle Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. Local regulator diffuses through extracellular fluid. Target cell is stimulated. (b) Synaptic signaling with neurotransmitters (a) Paracrine signaling using local regulators

Long-distance signaling Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. (c) Endocrine (hormonal) signaling

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

Animation: Overview of Cell Signaling Right-click slide / select “Play” © 2011 Pearson Education, Inc. 23

EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6-1 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6 Overview of cell signaling. Signaling molecule

Relay molecules in a signal transduction pathway Figure 11.6-2 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. Signaling molecule

Relay molecules in a signal transduction pathway Summary of chapter EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. 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 G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors © 2011 Pearson Education, Inc.

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 Signaling molecule binding site Segment that interacts with G proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors G protein-coupled receptor

Note: the enzyme is activated by shape change Figure 11.7b Note: the enzyme is activated by shape change G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme GTP GDP GDP CYTOPLASM G protein (inactive) Enzyme 1 2 GDP GTP Activated enzyme Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors GTP GDP P i 3 Cellular response 4

The structure of a G Protein-Coupled Receptor Consider…how would a mutation lead to disease? 2-adrenergic receptors Molecule resembling ligand Plasma membrane Figure 11.8 Impact: Determining the Structure of a G Protein-Coupled Receptor (GPCR) Cholesterol

2. Receptor tyrosine kinase Signaling molecule (ligand) Ligand-binding site  helix in the membrane Signaling molecule Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr CYTOPLASM Receptor tyrosine kinase proteins (inactive monomers) Dimer 1 2 Activated relay proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors Cellular response 1 Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Cellular response 2 Tyr Tyr P Tyr Tyr P Tyr Tyr P 6 ATP 6 ADP P Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Inactive relay proteins 3 4

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 2 3 Gate closed Ions Gate open Gate closed Signaling molecule (ligand) Plasma membrane Ligand-gated ion channel receptor Cellular response Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors

Intracellular Receptors 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.

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA NUCLEUS CYTOPLASM

The goal of most lipid soluble ligands is… Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA 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 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.

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

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.

What other organic molecule do cAMP resemble? Figure 11.11 What other organic molecule do cAMP resemble? Adenylyl cyclase Phosphodiesterase Pyrophosphate H2O P P i ATP cAMP AMP Figure 11.11 Cyclic AMP. Why?

First messenger (signaling molecule such as epinephrine) Figure 11.12 First messenger (signaling molecule such as epinephrine) Adenylyl cyclase G protein G protein-coupled receptor GTP ATP Second messenger cAMP Figure 11.12 cAMP as a second messenger in a G protein signaling pathway. 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.

How calcium can be used by cells EXTRACELLULAR FLUID Plasma membrane Ca2 pump ATP Mitochondrion Nucleus CYTOSOL Ca2 pump Figure 11.13 The maintenance of calcium ion concentrations in an animal cell. Endoplasmic reticulum (ER) Ca2 pump ATP Key High [Ca2 ] Low [Ca2 ]

Animation: Signal Transduction Pathways Right-click slide / select “Play” © 2011 Pearson Education, Inc. 50

Figure 11.14-1: Calcium and IP3 in signaling pathways EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Endoplasmic reticulum (ER) Ca2 CYTOSOL

Signaling molecule (first messenger) Figure 11.14-2 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Endoplasmic reticulum (ER) Ca2 Ca2 (second messenger) CYTOSOL

Signaling molecule (first messenger) Figure 11.14-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Various proteins activated Cellular responses Endoplasmic reticulum (ER) Ca2 Ca2 (second messenger) CYTOSOL

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.

Inactive transcription factor Active transcription factor Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 11.15 Nuclear responses to a signal: the activation of a specific gene by a growth factor. Response P DNA Gene NUCLEUS mRNA

Glucose 1-phosphate (108 molecules) Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein 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) Figure 11.16 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. 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.

What is this showing? RESULTS Wild type yeast (with shmoos) Fus3 formin CONCLUSION 1 Mating factor activates receptor. Mating factor Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit GTP P GDP 2 Phosphory- lation cascade G protein binds GTP and becomes activated. Formin Formin Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? P 4 Fus3 phos- phorylates formin, activating it. Microfilament Fus3 Fus3 P 5 Formin initiates growth of microfilaments that form the shmoo projections. 3 Phosphorylation cascade activates Fus3, which moves to plasma membrane.

Wild type (with shmoos) Figure 11.17a Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? Wild type (with shmoos)

Fine-Tuning of the Response There are four aspects of fine-tuning to consider: Amplification of 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.

Figure 11.18 The specificity of cell signaling. Signaling molecule Receptor Relay molecules Activation or inhibition Figure 11.18 The specificity of cell signaling. 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 Figure 11.19 Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Signaling molecule Plasma membrane Receptor Three different protein kinases Figure 11.19 A scaffolding protein. 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 Figure 11.20 Apoptosis of a human white blood cell. 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.

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

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

REVIEW 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules Figure 11.UN01 Summary figure, Concept 11.1 Signaling molecule