Cell Communication Chapter 11 Lectures prepared by Dr. Jorge L. Alonso Florida International University

Overview: The Cellular Internet Cell-to-cell communication is essential for multicellular organisms

Overview: The Cellular Internet 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

Communication between mating yeast cells Concept 11.1: External signals are converted to responses within the cell  factor Receptor 1 Exchange of mating factors a  Biologists have discovered some universal mechanisms of cellular regulation Microbes are a window on the role of cell signaling in the evolution of life 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/

Evolution of Cell Signaling Communication among bacteria Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling molecules allows bacteria to detect population density 1 Individual rod- shaped cells 0.5 mm 2 Aggregation in process Figure 11.3 Communication among bacteria 3 Spore-forming structure (fruiting body) Fruiting bodies

Local Signaling Plasma membranes 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 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

Local Signaling In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances 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 communication in animals Local regulator diffuses through extracellular fluid Target cell is stimulated (a) Paracrine signaling (b) Synaptic signaling

Long-Distance Signaling In long-distance signaling, plants and animals use chemicals called hormones: a signaling chemical produced by a gland, released into the bloodstream, and affecting an organ (target) in another part of the body Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Figure 11.5 Local and long-distance cell communication in animals Target cell 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 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 1 Reception Receptor Figure 11.6 Overview of cell signaling Signaling molecule

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

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 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Figure 11.6 Overview of cell signaling Activation of cellular response Relay molecules in a signal transduction pathway Signaling molecule

Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape Most signal receptors are plasma membrane proteins, a few are intracellular, found in the cytosol or nucleus of the cell 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

Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane

Receptors in the Plasma Membrane G-proteins There are three main types of membrane receptors: G protein-coupled receptors: the G-protein acts as on/off switch Receptor tyrosine kinases: attach phosphates to tyrosines which triggers a response Ion channel receptors: act as agate, allowing molecules or ions to enter cell

Signaling-molecule binding site Fig. 11-7a Signaling-molecule binding site Figure 11.7 Membrane receptors—G protein-coupled receptors, part 1 Segment that interacts with G proteins G protein-coupled receptor

Ligand (Signalling molecule) A G protein-coupled receptor 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

Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

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 1 Signaling molecule (ligand) Gate closed Ions Plasma membrane Ligand-gated ion channel receptor 2 Gate open Figure 11.7 Membrane receptors—ion channel receptors Cellular response 3 Gate closed

Intracellular Receptors Hormone (testosterone) EXTRACELLULAR FLUID Some receptor proteins are intracellular, 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 Plasma membrane Receptor protein Figure 11.8 Steroid hormone interacting with an intracellular receptor DNA NUCLEUS CYTOPLASM

Intracellular Receptors Hormone (testosterone) EXTRACELLULAR FLUID Some receptor proteins are intracellular, 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 Plasma membrane Receptor protein Hormone- receptor complex Figure 11.8 Steroid hormone interacting with an intracellular receptor DNA NUCLEUS CYTOPLASM

Intracellular Receptors Hormone (testosterone) EXTRACELLULAR FLUID Some receptor proteins are intracellular, 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 Plasma membrane Receptor protein Hormone- receptor complex Figure 11.8 Steroid hormone interacting with an intracellular receptor DNA NUCLEUS CYTOPLASM

Intracellular Receptors Hormone (testosterone) EXTRACELLULAR FLUID Some receptor proteins are intracellular, 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 Plasma membrane Receptor protein Hormone- receptor complex Figure 11.8 Steroid hormone interacting with an intracellular receptor DNA mRNA NUCLEUS CYTOPLASM

Intracellular Receptors Hormone (testosterone) EXTRACELLULAR FLUID Some receptor proteins are intracellular, 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 Plasma membrane Receptor protein Hormone- receptor complex Figure 11.8 Steroid hormone interacting with an intracellular receptor DNA 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

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

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

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

Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation Figure 11.9 A phosphorylation cascade This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

Small Molecules and Ions as Second Messengers First messenger The extracellular signal molecule 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 Adenylyl cyclase G protein G protein-coupled receptor GTP ATP Second messenger Figure 11.11 cAMP as second messenger in a G-protein-signaling pathway cAMP Protein kinase A Cellular responses

Small Molecules and Ions as Second Messengers First messenger Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases Cyclic AMP and calcium ions are common second messengers Adenylyl cyclase G protein G protein-coupled receptor GTP ATP Second messenger Figure 11.11 cAMP as second messenger in a G-protein-signaling pathway cAMP Protein kinase A Cellular responses

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 Figure 11.10 Cyclic AMP Adenylyl cyclase Phosphodiesterase Pyrophosphate P P i ATP cAMP 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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Calcium Ions and Inositol Triphosphate (IP3) EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) Figure 11.12 The maintenance of calcium ion concentrations in an animal cell Ca2+ pump ATP Key High [Ca2+] Low [Ca2+]

Calcium Ions and Inositol Triphosphate (IP3) EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion 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 Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) Figure 11.12 The maintenance of calcium ion concentrations in an animal cell Ca2+ pump ATP Key High [Ca2+] Low [Ca2+]

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 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ CYTOSOL

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 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL

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 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Various proteins activated Cellular responses 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” Figure 11.14 Nuclear responses to a signal: the activation of a specific gene by a growth factor Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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 may involve action 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 may function as a transcription factor Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Concept 11.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM The cell’s response to an extracellular signal is sometimes called the “output response” Figure 11.14 Nuclear responses to a signal: the activation of a specific gene by a growth factor Inactive transcription factor Active transcription factor Response P DNA Gene NUCLEUS mRNA

Nuclear and Cytoplasmic Responses Growth factor Reception Receptor Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Phosphorylation cascade Transduction CYTOPLASM Figure 11.14 Nuclear responses to a signal: the activation of a specific gene by a growth factor Inactive transcription factor Active transcription factor Response P DNA Gene NUCLEUS mRNA

Nuclear and Cytoplasmic Responses Growth factor Reception Receptor 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 may function as a transcription factor Phosphorylation cascade Transduction CYTOPLASM Figure 11.14 Nuclear responses to a signal: the activation of a specific gene by a growth factor Inactive transcription factor Active transcription factor Response P DNA Gene NUCLEUS mRNA

Other pathways regulate the activity of enzymes Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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 11.15 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 physical characteristics of a cell, for example, cell shape Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

RESULTS CONCLUSION Fig. 11-16 Wild-type (shmoos) ∆Fus3 ∆formin CONCLUSION Mating factor 1 Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit Figure 11.16 How do signals induce directional cell growth in yeast? GTP P GDP 2 Phosphory- lation cascade Formin Formin P 4 Microfilament Fus3 Fus3 P 5 3

Wild-type (shmoos) ∆Fus3 ∆formin RESULTS Fig. 11-16a Figure 11.16 How do signals induce directional cell growth in yeast? Wild-type (shmoos) ∆Fus3 ∆formin

CONCLUSION Mating factor Shmoo projection forming G protein-coupled Fig. 11-16b CONCLUSION Mating factor 1 Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit GTP P GDP 2 Phosphory- lation cascade Formin Formin P 4 Figure 11.16 How do signals induce directional cell growth in yeast? Microfilament Fus3 Fus3 P 5 3

Fine-Tuning of the Response Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Contributing to the specificity of the response Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Enzyme cascades amplify the cell’s response 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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Fig. 11-17 Figure 11.17 The specificity of cell signaling Signaling molecule Receptor Relay molecules Response 1 Response 2 Response 3 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Figure 11.17 The specificity of cell signaling Activation or inhibition Response 4 Response 5 Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

Cell B. Pathway branches, leading to two responses. Fig. 11-17a Signaling molecule Receptor Relay molecules Figure 11.17 The specificity of cell signaling Response 1 Response 2 Response 3 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses.

Cell C. Cross-talk occurs between two pathways. Fig. 11-17b Activation or inhibition Figure 11.17 The specificity of cell signaling Response 4 Response 5 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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Signaling Plasma molecule membrane Receptor Three different protein Fig. 11-18 Signaling molecule Plasma membrane Receptor Three different protein kinases Figure 11.18 A scaffolding protein Scaffolding protein

Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling When signal molecules leave the receptor, the receptor reverts to its inactive state Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Apoptosis is programmed or controlled cell suicide Concept 11.5: Apoptosis (programmed cell death) integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide A cell is chopped and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Apoptosis of human white blood cells Figure 11.19 Apoptosis of human white blood cells 2 µm

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 first studied in Caenorhabditis elegans In C. elegans, apoptosis results when specific proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Figure 11.20 Molecular basis of apoptosis in C. elegans Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4 Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal Ced-9 (inactive) Cell forms blebs Death- signaling molecule Figure 11.20 Molecular basis of apoptosis in C. elegans Active Ced-4 Active Ced-3 Other proteases Nucleases Activation cascade (b) Death signal

Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4 Fig. 11-20a Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Figure 11.20 Molecular basis of apoptosis in C. elegans Ced-4 Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal

Ced-9 (inactive) Cell forms blebs Death- signaling molecule Active Fig. 11-20b Ced-9 (inactive) Cell forms blebs Death- signaling molecule Active Ced-4 Active Ced-3 Other proteases Nucleases Figure 11.20 Molecular basis of apoptosis in C. elegans Activation cascade (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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Interdigital tissue 1 mm Fig. 11-21 Figure 11.21 Effect of apoptosis during paw development in the mouse

Reception Transduction Response Receptor Activation of cellular Fig. 11-UN1 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules Signaling molecule

Fig. 11-UN2

How do the effects of Viagra (multicolored) result from its inhibition of a signaling-pathway enzyme (purple)? Figure 11.1 How do the effects of Viagra (multicolored) result from its inhibition of a signaling-pathway enzyme (purple)?

You should now be able to: Describe the nature of a ligand-receptor interaction and state how such interactions initiate a signal-transduction system Compare and contrast G protein-coupled receptors, tyrosine kinase receptors, and ligand-gated ion channels List two advantages of a multistep pathway in the transduction stage of cell signaling Explain how an original signal molecule can produce a cellular response when it may not even enter the target cell Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

Define the term second messenger; briefly describe the role of these molecules in signaling pathways Explain why different types of cells may respond differently to the same signal molecule Describe the role of apoptosis in normal development and degenerative disease in vertebrates Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings