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.

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 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, 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 © 2011 Pearson Education, Inc.

Yeast cell, mating type a Yeast cell, mating type  Figure 11.2  factor Receptor 1 Exchange of mating factors 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/

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 © 2011 Pearson Education, Inc.

Individual rod-shaped cells Figure 11.3 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 Figure 11.4 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

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.

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. (a) Paracrine signaling (b) Synaptic signaling

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: A Preview Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response Animation: Overview of Cell Signaling © 2011 Pearson Education, Inc.

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 Figure 11.6-3 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 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.

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

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

2-adrenergic receptors Molecule resembling ligand Figure 11.8 2-adrenergic receptors Molecule resembling ligand Plasma membrane Figure 11.8 Impact: Determining the Structure of a G Protein-Coupled Receptor (GPCR) Cholesterol

Abnormal functioning of RTKs is associated with many types of cancers 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) Ligand-binding site Figure 11.7c 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

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 Ca2+, through a channel in the receptor © 2011 Pearson Education, Inc.

Signaling molecule (ligand) Figure 11.7d 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 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.

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

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-5 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 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 © 2011 Pearson Education, Inc.

Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations 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.

Activated relay molecule Figure 11.10 Signaling molecule 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

Activated relay molecule Figure 11.10a 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 Inactive protein kinase 3 ATP Figure 11.10 A phosphorylation cascade. ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein 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 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.

Figure 11.11 Adenylyl cyclase Phosphodiesterase Pyrophosphate AMP P i ATP cAMP AMP Figure 11.11 Cyclic AMP.

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.

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.

Endoplasmic reticulum (ER) Figure 11.13 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 ]

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 (IP3) and diacylglycerol (DAG) as additional second messengers Animation: Signal Transduction Pathways © 2011 Pearson Education, Inc.

Signaling molecule (first messenger) Figure 11.14-1 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 cell’s response to an extracellular signal is sometimes called the “output response” © 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.

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

Other pathways regulate the activity of enzymes rather than their synthesis © 2011 Pearson Education, Inc.

Glucose 1-phosphate (108 molecules) Figure 11.16 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.

Wild type (with shmoos) Fus3 formin CONCLUSION Figure 11.17 RESULTS Wild type (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.

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 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 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.

Three different protein kinases Figure 11.19 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 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 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 (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 © 2011 Pearson Education, Inc.

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