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Chapter 11
Cell Communication
Overview: The Cellular Internet
Cell-to-cell communication is essential for multicellular organisms
Biologists have discovered some universal mechanisms of cellular regulation
The combined effects of multiple signals determine cell response
For example, the dilation of blood vessels is controlled by multiple molecules
Viagra
Microbes are a window on the role of cell signaling in the evolution of life
Figure 11.1
Evolution of Cell Signaling
Yeast cells identify their mates by cell signaling
factorReceptor
Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type.
1
Mating. Binding of the factors to receptors induces changes in the cells that lead to their fusion.
New a/ cell. The nucleus of the fused cell includes all the genes from the a and a cells.
2
3
factorYeast cell,mating type a
Yeast cell,mating type
a/
a
a
Figure 11.2
Signal transduction pathways
Convert specific signals on a cell’s surface into cellular responses
Often a series of steps
Molecular details of signal transduction in yeast, mammals, bacteria and plants are very similar...
Evolution of signal transduction pathways
Even though the last common ancestor was over a billion years ago
This suggest early versions of cell signaling developed in the ancient prokaryotes
Before first multicellular organisms
Fig. 11-3
Individual rod-shaped cells
Spore-formingstructure(fruiting body)
Aggregation inprocess
Fruiting bodies
0.5 mm
1
3
2
Local and Long-Distance and Signaling
Cells in a multicellular organism Usually communicate via chemical
messengers
Direct contact Local signaling Long-distance signaling
Direct contact - Cell junctions Animal and plant cells can directly
connect the cytoplasm of adjacent cells Plasma membranes
Plasmodesmatabetween plant cells
Gap junctionsbetween animal cells
Figure 11.3 (a) Cell junctions. Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes.
Figure 11.3 (b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces.
Direct contact - Cell-cell recognition In local signaling, animal cells may
communicate via direct contact
Local – Paracrine & Synaptic
Animal cells communicate using local regulators
(a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid.
(b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell.
Local regulator diffuses through extracellular fluid
Target cell
Secretoryvesicle
Electrical signalalong nerve celltriggers release ofneurotransmitter
Neurotransmitter diffuses across
synapse
Target cellis stimulated
Local signaling
Figure 11.4 A B
Long-distance signaling
Both plants and animals use hormones
Hormone travelsin bloodstreamto target cells
(c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells.
Long-distance signaling
Bloodvessel
Targetcell
Endocrine cell
Figure 11.4 C
The Three Stages of Cell Signaling: A Preview
Earl W. Sutherland Discovered how the hormone
epinephrine acts on cells
Epinephrine stimulates glycogen breakdown
The enzyme (glycogen phosphorylase) does not work with an intact cellular membrane
Cellular conversation
Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response
Animation: Overview of Cell SignalingAnimation: Overview of Cell Signaling
EXTRACELLULARFLUID
Receptor
Signal molecule
Relay molecules in a signal transduction pathway
Plasma membraneCYTOPLASM
Activationof cellularresponse
Figure 11.5
Overview of cell signaling
Reception1 Transduction2 Response3
Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape
The binding between signal molecule (ligand) And receptor is highly specific
A conformational 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 receptor proteins in membrane
There are three main types of membrane receptors G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors
G protein-coupled receptors
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
Fig. 11-7b
G protein-coupledreceptor
Plasmamembrane
EnzymeG protein(inactive)
GDP
CYTOPLASM
Activatedenzyme
GTP
Cellular response
GDP
P i
Activatedreceptor
GDP GTP
Signaling moleculeInactiveenzyme
1 2
3 4
G protein-coupled receptors
Large family of eukaryotic receptor proteins They function is diverse and widespread For example, embryo development and
sensory reception Bacteria like cholera, pertussis and
botulism interfere with G-protein function 60% of all medicines exert effects on G-
proteins
Receptor tyrosine kinasesSignalmolecule
Signal-binding sitea
CYTOPLASM
Tyrosines
Signal moleculeHelix in the
Membrane
Tyr
Tyr
Tyr
Tyr
Tyr
TyrTyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
DimerReceptor tyrosinekinase proteins(inactive monomers)
P
P
PP
P
P Tyr
Tyr
Tyr
Tyr
Tyr
TyrP
P
P
P
P
PCellularresponse 1
Inactiverelay proteins
Activatedrelay proteins
Cellularresponse 2
Activated tyrosine-kinase regions(unphosphorylateddimer)
Fully activated receptortyrosine-kinase(phosphorylateddimer)
6 ATP 6 ADP
Figure 11.7
Receptor tyrosine kinases
Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines
They may activate 10 or more different transduction pathways and cellular responses
Abnormal receptor tyrosine kinases may contribute to some cancers
Ion channel receptors
Signalingmolecule(ligand)
Gateclosed Ions
Ligand-gatedion channel receptor
Plasmamembrane
Gate open
Cellularresponse
Gate closed3
2
1
Ligand-gated ion channel
The gate allows or blocks the flow of specific ions, such as Na+ and Ca2+
Important in the nervous system The signal molecule can be a ligand
(as shown in the picture) or an electrical signal
Intracellular Receptors
Intracellular receptors Are cytoplasmic or nuclear proteins
Signal molecules that are small or hydrophobic And can readily cross the plasma
membrane use these receptors
Hormone(testosterone)
EXTRACELLULARFLUID
Receptorprotein
DNA
mRNA
NUCLEUS
CYTOPLASM
Plasmamembrane
Hormone-receptorcomplex
New protein
Figure 11.6
Steroid hormones
Bind to intracellular receptors
The testosterone receptor acts as a transcription factor
Most intracellular receptors work this way
1 The steroid hormone testosterone passes through the plasma membrane.
The bound proteinstimulates thetranscription ofthe gene into mRNA.
4
The mRNA istranslated into aspecific protein.
5
Testosterone bindsto a receptor proteinin the cytoplasm,activating it.
2
The hormone-receptor complexenters the nucleusand binds to specific genes.
3
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
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
Protein phosphorylation & 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
Cytoplasmic protein kinases phosphorylate either amino acid serine or threonine (rather than tyrosine)
Serine/threonine kinases are involved in signaling pathways in animals, plants and fungi
In this process
A series of protein kinases add a phosphate to the next one in line, activating it
Protein phosphatase (PP) enzymes then remove the phosphates
Phosphorylation/dephosphorylation system acts as a molecular switch turning activities on and off
Signal molecule
Activeproteinkinase
1
Activeproteinkinase
2
Activeproteinkinase
3
Inactiveprotein kinase
1
Inactiveprotein kinase
2
Inactiveprotein kinase
3
Inactiveprotein
Activeprotein
Cellularresponse
Receptor
P
P
P
ATPADP
ADP
ADP
ATP
ATP
PP
PP
PP
Activated relaymolecule
i
Phosphorylation cascade
P
P
i
i
P
A phosphorylation cascade
Figure 11.8
A relay moleculeactivates protein kinase 1.
1
2 Active protein kinase 1transfers a phosphate from ATPto an inactive molecule ofprotein kinase 2, thus activatingthis second kinase.
Active protein kinase 2then catalyzes the phos-phorylation (and activation) ofprotein kinase 3.
3
Finally, active proteinkinase 3 phosphorylates aprotein (pink) that brings about the cell’s response tothe signal.
4 Enzymes called proteinphosphatases (PP)catalyze the removal ofthe phosphate groupsfrom the proteins, making them inactiveand available for reuse.
5
Small Molecules and Ions as Second Messengers
Second messengers Are small, nonprotein, water-soluble
molecules or ions
Two most widely used second messengers are: Cyclic AMP (cAMP) Calcium ions, Ca2+
Cyclic AMP
Cyclic AMP (cAMP) Is made from ATP
Figure 11.9
O–O O
O
N
O
O
O
O
P P P
P
P P
O
O
O
O
O
OH
CH2
NH2 NH2 NH2
N
N
N
N
N
N
N
N
N
N
NO
O
O
ATP
Ch2CH2
O
OH OH
P
O O
H2O
HOAdenylyl cyclase Phoshodiesterase
Pyrophosphate
Cyclic AMP AMPOH OH
O
i
ATP
GTP
cAMP
Proteinkinase A
Cellular responses
G-protein-linkedreceptor
AdenylylcyclaseG protein
First messenger(signal moleculesuch as epinephrine)
Many G-proteins Trigger the
formation of cAMP, which then acts as a second messenger in cellular pathways
Figure 11.10
Calcium ions and Inositol Triphosphate (IP3)
Ca2+, when released into the cytosol of a cell Acts as a second messenger Animal cells – muscle contraction,
secretion of certain substances and cell division
Plant cells – hormonal and environmental stimuli can cause changes in Ca2+ concentration signaling various pathways
Calcium is an important second messenger
Because cells are able to regulate its concentration in the cytosol
EXTRACELLULARFLUID
Plasmamembrane
ATP
CYTOSOL
ATP Ca2+
pump
Ca2+
pump
Ca2+
pump
Endoplasmicreticulum (ER)
Nucleus
Mitochondrion
Key High [Ca2+] Low [Ca2+]Figure 11.11
Other second messengers
Such as inositol triphosphate (IP3) and diacylglycerol (DAG) Can trigger an increase in calcium in the
cytosol
Animation: Signal Transduction PathwaysAnimation: Signal Transduction Pathways
Fig. 11-13-3
G protein
EXTRA-CELLULARFLUID
Signaling molecule(first messenger)
G protein-coupledreceptor Phospholipase C PIP2
DAG
IP3
(second messenger)
IP3-gatedcalcium channel
Endoplasmicreticulum (ER) Ca2+
CYTOSOL
Variousproteinsactivated
Cellularresponses
Ca2+
(secondmessenger)
GTP
Cytoplasmic & nuclear responses
In the cytoplasm Signaling pathways regulate a variety of
cellular activities They regulate the activity of enzymes They also 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
Nuclear responses to a signal
Regulate genes by activating transcription factors that turn genes on or off
Reception
Transduction
Response
mRNANUCLEUS
Gene
P
Activetranscriptionfactor
Inactivetranscriptionfactor
DNA
Phosphorylationcascade
CYTOPLASM
Receptor
Growth factor
Figure 11.14
Cytoplasmic response to a signal
Figure 11.13 Glucose-1-phosphate(108 molecules)
Glycogen
Active glycogen phosphorylase (106)
Inactive glycogen phosphorylase
Active phosphorylase kinase (105)
Inactive phosphorylase kinase
Inactive protein kinase A
Active protein kinase A (104)
ATPCyclic AMP (104)
Active adenylyl cyclase (102)
Inactive adenylyl cyclase
Inactive G protein
Active G protein (102 molecules)
Binding of epinephrine to G-protein-linked receptor (1 molecule)
Transduction
Response
Reception
Regulating the activity of enzymes
The stimulation of glycogen breakdown by epinephrine
Signaling events may also affect cellular attributes
such as overall cell shape. One example of this regulation can be
found in the activities leading to the mating of yeast cells.
In yeast, the mating process depends on the growth of localized projections in one cell toward a cell of the opposite mating type.
Fig. 11-16 RESULTS
CONCLUSION
Wild-type (shmoos) ∆Fus3 ∆formin
Shmoo projection forming
ForminP
ActinsubunitP
PForminFormin
Fus3
Phosphory- lation cascade
GTP
G protein-coupledreceptor
Matingfactor
GDP
Fus3 Fus3
P
Microfilament
1
2
3
4
5
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
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
The Specificity of Cell Signaling
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
Specificity of cell signaling
Response 1
Response 4 Response 5
Response
2
Response
3
Signalmolecule
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 receptorleads to a different response
Activationor inhibition
Receptor
Relaymolecules
Figure 11.15
Epinephrine
A small number of epinephrine molecules can lead to the release of hundreds of millions of glucose molecules from glycogen
Epinephrine stimulates the liver to break down glycogen, but the heart cell to contract
Signaling Efficiency: Scaffolding Proteins & 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
Signaling Efficiency: Scaffolding Proteins and Signaling Complexes
Scaffolding proteins Can increase the signal transduction
efficiencySignalmolecule
Receptor
Scaffoldingprotein
Threedifferentproteinkinases
Plasmamembrane
Figure 11.16
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
Fig. 11-19
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
Fig. 11-20
Ced-9protein (active)inhibits Ced-4activity
Mitochondrion
Receptorfor death-signalingmolecule
Ced-4 Ced-3
Inactive proteins
(a) No death signal
Ced-9(inactive)
Cellformsblebs
Death-signalingmolecule
Otherproteases
ActiveCed-4
ActiveCed-3
NucleasesActivationcascade
(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
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
You should now be able to:
1. Describe the nature of a ligand-receptor interaction and state how such interactions initiate a signal-transduction system
2. Compare and contrast G protein-coupled receptors, tyrosine kinase receptors, and ligand-gated ion channels
3. List two advantages of a multistep pathway in the transduction stage of cell signaling
4. Explain how an original signal molecule can produce a cellular response when it may not even enter the target cell
5. Define the term second messenger; briefly describe the role of these molecules in signaling pathways
6. Explain why different types of cells may respond differently to the same signal molecule
7. Describe the role of apoptosis in normal development and degenerative disease in vertebrates