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