Chapter 11

CellComm

•atia

KEY CONCEPTS

11.1 External signals are converted to responseswithin the cell

11.2 Reception: Asignaling molecule hinds to areceptor protein, causing it to change shape

11.3 Transduction: Cascades of molecularinteractions relay signals from receptors totarget molecules in the cell

11.4 Response: Cell signaling leads to regulation oftranscription or cytoplasmic activities

11.5 Apoptosis (programmed cell death) integratesmultiple cell-signaling pathways

Ahiker slips and falls down a steep ravine, injuringher leg in the fall. Tragedy is averted when she isable to pull out a cell phone and call for help. Cell

phones, the Internet, e-mail, instant messaging-no onewould deny the importance of communication in our lives.The role of communication in life at the cellular level isequally critical. Cell-to-cell communication is absolutely essential for multicellular organisms such as humans and oaktrees. The trillions of cells in a multicellular organism mustcommunicate with each other to coordinate their activitiesin a way that enables the organism to develop from a fertilized egg, then survive and reproduce in turn. Communication between cells is also important for many unicellularorganisms. Networks of communication between cells canbe even more complicated than the World Wide Web.

In studying how cells signal to each other and how they interpret the signals they receive, biologists have discovered someuniversal mechanisms ofcellular regulation, additional evidencefor the evolutionary relatedness ofall life. The same small set ofcell-signaling mechanisms shows up again and again in many

206

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

lines of biological research-from embryonic development tohormone action to cancer. In one example, a common cell-tocell signaling pathway leads to dilation ofblood vessels. Once thesignal subsides, the response is shut down by the enzyme shownin purple in Figure 11.1. Also shown isa multicolored moleculethat blocks the action ofthis enzyme and keeps blood vessels dilated. Enzyme-inhibiting compounds like this one are often prescribed for treatment of medical conditions. The action of themulticolored compound, known as Viagra, will be discussedlater in the chapter. The signals received by cells, whether originating from other cells or from changes in the physical environment, take various forms, including light and touch. However,cells most often communicate with each other by chemical signals. In this chapter, we focus on the main mechanisms by whichcells receive, process, and respond to chemical signals sent fromother cells. At the end, we will take a look at apoptosis, a type ofprogrammed cell death that integrates input from multiple signaling pathways.

r;:~:tr~'a7 s~:~~ls are converted toresponses within the cell

What does a "talking" cell say to a ~listeningn cell, and howdoes the latter cell respond to the message? Let's approachthese questions by first looking at communication among microorganisms, for modern microbes are a window on the roleof cell signaling in the evolution oflife on Earth.

Evolution of Cell SignalingOne topic of cell "conversation" is sex-at least for the yeastSaccharomycescerevisiae, which people have used for millennia to make bread, wine, and beer. Researchers have learned

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... Figure 11.2 Communication between mating yeastcells. saccharomyces cerevisiae cells use chemICal signaling to Identifycells of opposite mating type and initiate the mating process, The twomating types and their corresponding chemical signaling molecules. ormating factors. are called a and n,

oAggregation in process

JJ

Fruiting bodies

oSpore-forming structure(fruiting body)

and others more recently uncovered between signaling systems in bacteria and plants-suggest that early versions ofthe cell-signaling mechanisms used today evolved well before the first multicellular creatures appeared on Earth.

Scientists think that signaling mechanisms first evolved in ancient prokaryotes and single-celled eukaryotes and then wereadopted for new uses by their multicellular descendants. Meanwhile, cell signaling has remained important in the microbialworld. Cells of many bacterial species secrete small moleculesthat can be detected by other bacterial cells. The concentrationof such signaling molecules allows bacteria to sense the localdensity of bacterial cells, a phenomenon called quorum sensing.Furthermore, signaling among members of a bacterial population can lead to coordination oftheir activities. In response to thesignal, bacterial cells are able to come together and form bioji/ms,aggregations ofbacteria that often form recogni7.able structurescontaining regions of specialized function. Figure 11.3 showsan aggregation response characteristic ofone type ofbacterium.

... Figure 11.3 Communication among bacteria. Soil-d'wellingbacteria called myxobactena ("slime bacteria") use chemical Signals toshare information about nutrient a~ailability, When food is scarce, starvingcells secrete a molecule that reaches neighboring cells and stimulatesthem to aggregate. The cells form a structure, called a fruiting body, thatproduces thick-walled spores capable of surviving until the environmentimpro~es. The bacteria shown here are Myxococcus xanrhus (steps 1-3,SEMs; lower photo. lM)

Yeast cell.mating type 0:

a:" factor

F•

Yeast cell.mating type a

() New ala cell.The nucleus ofthe fused cellincludes all thegenes from thea and a cells.

8 Mating. Bindingof the factors toreceptorsinduces changesin the cells thatlead to theirfusion.

o Exchange ofmating factors.Each cell typesecretes amating factorthat binds toreceptors on theother cell type.

that cells of this yeast identify their mates by chemical signaling. There are two sexes, or mating types, called a and 0:

(Figure 11.2). Cells of mating type a secrete a signaling moleculecalled a factor, which can bind to specific receptor proteinson nearby 0: cells. At the same time, 0: cells secrete a factor,which binds to receptors on a cells. \Vithout actually enteringthe cells, the two mating factors cause the cells to grow towardeach other and also bring about other cellular changes. The result is the fusion, or mating, of two cells of opposite type. Thenew a/o: cell contains all the genes of both original cells, a combination of genetic resources that provides advantages to thecell's descendants, which arise by subsequent cell divisions.

How is the mating signal at the yeast cell surface changed,or transduced, into a form that brings about the cellular response of mating? The process by which a signal on a cell'ssurface is converted to a specific cellular response is a seriesof steps called a signal transduction pathway. Many suchpathways have been extensively studied in both yeast and animal cells. Amazingly, the molecular details of signal transduction in yeast and mammals are strikingly similar, eventhough the last common ancestor of these two groups oforganisms lived over a billion years ago. These similarities-

C~APTE~ ELEVE~ Cell Communication 207

Plasma membranes

and plants have cell junctions that, where present, directly connect the cytoplasms of adjacent cells (Figure 11.4a). In thesecases, signalingsubstancesdissolved in the cytosol can pass freelybem'een adjacent cells. Moreover, animal cells may communicatevia direct contact between membrane~bound cell~surface mol·ecules, which occurs during a process called cell-cell recognition(Figure 11.4b). This sort of signaling is important in suchprocesses as embryonic development and the immune response.

In many other cases, messenger molecules are secreted bythe signaling cell. Some of these travel only short distances;such local regulators influence cells in the vicinity. One classof local regulators in animals,growlhfactors, consists of compounds that stimulate nearby target cells to grow and divide.Numerous cells can simultaneously receive and respond to themolecules of growth factor produced by a single cell in theirvicinity. This type of local signaling in animals is calledparacrine signaling (Figure 11.5a).

Another, more specialized type of local signaling calledsynaptic signaling occurs in the animal nervous system(Figure 11.5b). An electrical signal along a nerve cell triggersthe secretion of a chemical signal carried by neurotransmittermolecules. These diffuse across the synapse, the narrow spacebem'een the nerve cell and its target cell (often another nervecell). The neurotransmitter stimulates the target cell.

Local signaling in plants is not as well understood. Becauseof their cell walls, plants use mechanisms somewhat differentfrom those operating locally in animals.

Both animals and plants use chemicals called hormonesfor long-distance signaling. In hormonal signaling in animals,also known as endocrine signaling, specialized cells release

Plasmodesmatabetween plant cells

-+,+j-'

Gap junctionsbetween animal cells

(b) Cell-cell recognition. Two cells in an animal may communicateby interaction between molecules protruding from their surfaces.

(a) Cell junctions. Both animals and plants have cell Junctions thaIallow molecules to pass readily between adjacent cells withoutcrossing plasma membranes.

local and long-Distance Signaling

Like yeast cells, cells in a multicellular organism usually communicate via chemical messengers targeted for cells that mayor maynot be immediately adjacent. As we saw in Chapters 6and 7, cellsmay communicate by direct contact (Figure 11.4), Both animals

.... Figure 11.4 Communication by direct contact betweencells.

Target -ceil

/

Long-distance signaling

..". ,.''-'-'-'' ...

Endocrine cell\

tt~~. '...;g ••..

(e) Hormonal signaling. Specialized endocrinecells secrete hormones into body fluids. oftenthe blood. Hormones may reach virtually allbody cells.

Target cellis stimulated

(b) Synaptk signaling. A nerve cell releasesneurotransmitter molecules into asynapse. stimulating the target cell

••~ .~~."if· .••'. '.

'. y •.~ .... .

Secreting _ ~cell

Local ~~lat;rdiffuses throughextracellular flUid

(a) Paracrine signaling. A secreting cell acts onnearby target cells by discharging moleculesof a local regulator (a growth factor. forexample) into the eKlraceliular fluid.

.&. Figure 11.5 Local and long-distance cell communication in animals. In bothlocal and long-distance signaling. only specific target cells recognize and respond to agivensignaling molecule.

Local signaling

~===-------=-=-,~---------,Target cell ijElectrical sign,'I along nerve cell

triggers release ofneurotransmitter

.::: :;;;.' ..:.~ •.•••• \ •• I.'.' : •~. t...!...... Neurotransmitter

1"',:.-0; Secretory '-'~~ diffuses acrossV; vesicle synapse

208 UNIT TWO The Cell

hormone molecules, which travel via the circulatory system totarget cells in other parts of the body (Figure 11.5c). Planthormones (often called plant growth regulators) sometimestravel in vessels but more often reach their targets by moving

through cells or by diffusing through the air as a gas (seeChapter 39). Hormones vary widely in molecular size and

type, as do local regulators. For instance, the plant hormoneethylene, a gas that promotes fruit ripening and helps regulategrowth, is a hydrocarbon of only six atoms (C:2H4), smallenough to pass through cell walls. In contrast, the mammalianhormone insulin, which regulates sugar levels in the blood, isa protein with thousands of atoms.

The transmission of a signal through the nervous system canalso be considered an example of long-distance signaling. Anelectrical signal travels the length ofa nerve cell and is then converted back to a chemical signal when a signaling mole<ule is re

leased and crosses the synapse to another nerve cell. Here it isconverted back to an electrical signal. In this way, a nerve signalcan travel along a series of nerve cells. Because some nerve cellsare quite long, the nerve signal can quickly travel great distances-from your brain to your big toe, for example. This type

oflong-distance signalingwiU be covered in detail in Chapter 48.What happens when a cell encounters a signaling mole

cule? The molecule must be recognized by a specific receptormolecule, and the information it carries, the signal, must bechanged into another form-transduced-inside the cell before the cell can respond. The remainder of the chapter discusses this process, primarily as it occurs in animal cells.

The Three Stages of Cell Signaling: A Preview

Our current understanding of how chemical messengers actvia signal transduction pathways had its origins in the pioneering work of Earl \Y/. Sutherland, whose research led to a NobelPrize in 1971. Sutherland and his colleagues at VanderbiltUniversity were investigating how the animal hormone epi

nephrine stimulates the breakdown of the storage polysaccha-

ride glycogen within liver cells and skeletal muscle cells.Glycogen breakdown releases the sugar glucose· I-phosphate,

which the cell converts to glucose-6-phosphate. The cell (aliver cell, for example) can then use this compound, an early

intermediate in glycolysis, for energy production. Alternatively, the compound can be stripped of phosphate and released from the liver cell into the blood as glucose, which canfuel cells throughout the body. Thus, one effect of epinephrine, which is secreted from the adrenal gland during times ofphysical or mental stress, is the mobilization of fuel reserves.

Sutherland's research team discovered that epinephrinestimulates glycogen breakdown by somehow activating acytosolic enzyme, glycogen phosphorylase. However, whenepinephrine was added to a test-tube mixture containing theenzyme and its substrate, glycogen, no breakdown occurred.

Epinephrine could activate glycogen phosphorylase onlywhen the hormone was added to a solution containing intactcells. This result told Sutherland two things. First, epinephrine does not interact directly with the enzyme responsiblefor glycogen breakdown; an intermediate step or series ofsteps must be occurring inside the cell. Second, the plasmamembrane is somehow involved in transmitting the epinephrine signal.

Sutherland's early work suggested that the process going onat the receiving end of a cellular conversation can be dissectedinto three stages: reception, transduction, and response(Figure 11.6):

o Reception. Reception is the target cell's detection of asignaling molecule coming from outside the cell. Achemical signal is "detected" when the signaling molecule binds to a receptor protein located at the cell's sur

face or inside the cell.e Transduction. The binding of the signaling molecule

changes the receptor protein in some way, initiating theprocess of transduction. The transduction stage converts the signal to a form that can bring about a specific

Relay molecules in a signal transduction pathway

--Plasma membrane

Acti~atlon

of cellularresponse

I0 Response I

--CYTOPLASM

--Ie Transduction

--I0 Reception

Receptor

(

Signalingmolecule

EXTRACELLULARflUID

.. Figure 11.6 Overview of cellsignaling. From the perspective of the cellreceiving the message, cell signaling can bedivided into thre€ stages: signal reception, signaltransduction. and cellular respoose, INhroreceptioo occurs at the plasma membrane, asshCM'n hefe. the transduction stage is usually apathway of several steps, with each relay moleculein the pathway bringing abolJt achange in ther1e)(( molecule. The final molecule ir1 the pathwaytriggers the cell's response, The three stages areexplained in more detail in the text.n How does the epinephrine in Sutherland's.. experiment fit into this diagram of cellSignaling?

C~APTE~ ELE~E~ CellCommunitation 209

cellular response. In Sutherland's system, the binding ofepinephrine to a receptor protein in a liver cell's plasmamembrane leads to activation of glycogen phosphorylase. Transduction sometimes occurs in a single step

but more often requires a sequence of changes in a se

ries of different molecules-a signal transduction pathway. The molecules in the pathway are often called relaymolecules.

€) Response. In the third stage of cell signaling, the transduced signal finally triggers a specific cellular response.The response may be almost any imaginable cellularactivity-such as catalysis by an enzyme (for example,glycogen phosphorylase), rearrangement of the cytoskeleton, or activation of specific genes in the nucleus.The cell-signaling process helps ensure that crucial activities like these occur in the right cells, at the right time,and in proper coordination with the other cells ofthe organism. We'll now explore the mechanisms of cell sig

naling in more detail.

CONCEPT CHECI( 11.1

ceptor and attaches there, like a key in a lock or a substratein the catalytic site of an enzyme. The signaling molecule behaves as a ligand, the term for a molecule that specificallybinds to another molecule, often a larger one. Ligand bind

ing generally causes a receptor protein to undergo a change

in shape. For many receptors, this shape change directly activates the receptor, enabling it to interact with other cellularmolecules. For other kinds of receptors, the immediate effectof ligand binding is to cause the aggregation of two or morereceptor molecules, which leads to further molecular eventsinside the cell.

In a general way, ligand binding is similar to the binding ofan allosteric regulator to an enzyme, causing a shape changethat either promotes or inhibits enzyme activity. In the case ofsignal transduction, binding of the ligand alters the ability ofthe receptor to transmit the signal.

Most signal receptors are plasma membrane proteins.Their ligands are water-soluble and generally too large to

pass freely through the plasma membrane. Other signal reoceptors, however, are located inside the cell. We discuss both

of these next.

1. Explain how signaling is involved in ensuring thatyeast cells only fuse with cells of the opposite matingtype.

2. Explain how nerve cells provide examples of bothlocal and long-distance signaling.

3. When epinephrine is mixed with glycogen phosphorylase and glycogen in a test tube, is glucose-I-phosphategenerated? Why or why not?

4, _IWUI. In liver cells, glycogen phosphorylase

acts in which of the three stages of the signaling pathway associated with an epinephrine-initiated signal?

For suggested answers, see Appendix A.

r::~:~~::~~ignaling moleculebinds to a receptor protein,causing it to change shape

\Vhen we speak to someone, others nearby may inadver·tently hear our message, sometimes with unfortunate conse·quences. However, errors of this kind rarely occur amongcells. The signals emitted by an a yeast cell are "heard~ only

by its prospective mates, a cells. Similarly, although epinephrine encounters many types of cells as it circulates in theblood, only certain target cells detect and react to the hormone. A receptor protein on or in the target cell allows thecell to "hearn the signal and respond to it. The signaling molecule is complementary in shape to a specific site on the re-


Receptors in the Plasma Membrane

Most water-soluble signaling molecules bind to specific siteson receptor proteins embedded in the cell's plasma memo

brane. Such a receptor transmits information from the extracellular environment to the inside of the cell by changingshape or aggregating when a specific ligand binds to it. We cansee how membrane receptors work by looking at three majortypes: G protein-coupled receptors, receptor tyrosine kinases,and ion channel receptors. These receptors are discussed andillustrated in Figure 11.7, on the next three pages; study thisfigure before going on.

Intracellular Receptors

Intracellular receptor proteins are found in either the cytoplasm or nucleus of target cells. To reach such a receptor, a chemical messenger passes through the target cell'splasma membrane. A number of important signaling molecules can do this because they are either hydrophobic

enough or small enough to cross the phospholipid interiorofthe membrane. Such hydrophobic chemical messengersinclude the steroid hormones and thyroid hormones ofan·imals. Another chemical signaling molecule with an intracellular receptor is nitric oxide (NO), a gas; its very smallmolecules readily pass between the membrane phospholipids.

The behavior of testosterone is representative of steroidhormones. Secreted by cells of the testis, the hormone travelsthrough the blood and enters cells all over the body. In the cytoplasm of target cells, the only cells that contain receptormolecules for testosterone, the hormone binds to the receptor

• Figure 11.1

•• • Membrane Receptors

G Protein-Coupled ReceptorsSignaling-molecule binding site

A G protein-coupled

receptor is a plasma

membrane receptor that

works with the help of aG protein, a protein that

binds the energy-rich

molecule GTP. Many

different signaling

molecules, including yeast

mating factors, epinephrine

and many other hormones,Gprotein-coupled receptor and neurotransmitters, use

G protein-coupled receptors.

These receptors vary in the binding sites for both their signalingmolecules (also called their ligands) and for different G proteins

inside the cell. Nevertheless, G protein-coupled receptor proteins

are all remarkably similar in structure. They each have seven 0:

helices spanning the membrane, as shown above.

A large family of eukaryotic receptor proteins has this

secondary structure, where the single polypeptide, representedhere as a ribbon, has seven transmembrane 0. helices,

represented as cylinders and depicted in a row for clarity.

Specific loops between the helices form binding sites for

signaling and G-protein molecules.

G protein-coupled receptor systems are extremely widespread and

diverse in their functions, including roles in embryonic developmentand sensory reception. [n humans, for example, both vision and

smell depend on such proteins. Similarities in structure among G

proteins and G protein-coupled receptors in diverse organisms

suggest that G proteins and associated receptors evolved very early.G-protein systems are involved in many human diseases,

including bacterial infections. The bacteria that cause cholera,

pertussis {whooping cough}. and botulism, among others. make their

victims ill by prOOucing toxins that interfere with G-protein function.

Pharmacologists now realize that up to 60% of all medicines usedtoday exert their effects by influencing G-protein pathways.

G protein-coupledreceptor

CYTOPLASM

Plasmamembrane

I

Gprotem(inactive)

Enzyme

Activatedreceptor

Inactiveenzyme

I

o loosely attached to the cytoplasmic side of the membrane, the Gprotem functions as a molecular switch that IS either on or off.depending on which of two guanine nucleotides is attached, GOPor GTP-hence the term Gprotein. (GTP, or guanosine triphosphate, is similar to ATP.) When GOP is bound to the Gprotein, asshown above, the G protein is inactive. The receptor and G proteinwork together with another protein. usually an enzyme

Activatedenzyme

I

Cellular response

o The activated G protein dissociates from the receptor, diffusesalong the membrane, and then binds to an enzyme, altering theenzyme; sh ape and activity. When the enzyme is activated, it cantrigger the next step ma pathway leading to acellular response

8 When the appropriate signaling molecule binds to the extracellularside of the receptor, the receptor is activated and changes shapeIts cytoplasmic side then binds an inactive Gprotein. causing a GTPto displace the GOP. This activates the Gprotein.

o The changes in the enzyme and Gprotem are only temporarybecause the G protein also functions as a GTPase enzyme-in otherwords, it then hydrolyzes its bound GTP to GOP. Now inactiveagain, the Gprotein leaves the enzyme, which returns to itsoriginal state. The G protein is now available for reuse. The GTPasefunction of the G protein allows the pathway to shut down rapidlywhen the signali ng molecule is no longer present.

Continued on next page

CHAPTH HEVEN Cell Communication 211

• Figure 11.7 (continued)

•• • Membrane Receptors

Receptor Tyrosine Kinases

Receptor tyrosine kinases belong to a major class of plasma

membrane receptors characterized by having enzymatic activity.

A kinase is an enzyme that catalyzes the transfer of phosphate

groups. The part of the receptor protein extending into the

cytoplasm functions as a tyrosine kinase, an enzyme that

catalyzes the transfer of a phosphate group from ATP to the

amino acid tyrosine on a substrate protein. Thus, receptor

tyrosine kinases are membrane receptors that attach phosphates

to tyrosines.

One receptor tyrosine kinase complex may activate ten ormore different transduction pathways and cellular responses.Often, more than one signal transduction pathway can betriggered at once, helping the cell regulate and coordinate manyaspects of cell growth and cell reproduction. The ability of asingle ligand-binding event to trigger so many pathways is a keydifference between receptor tyrosine kinases and G proteincoupled receptors. Abnormal receptor tyrosine kinases thatfunction even in the absence of signaling molecules maycontribute to some kinds of cancer.

Dimer

-ligand-binding site

Receptor tyrosinekinase proteins(inadive monomers)

Tyrosines

a Helix in themembrane

Signalingmolecule (ligand)

CYTOPLASM

G Many receptor tyrosine kinase, have the structure depictedschematically here Sefore the signaling molecule binds. thereceptors exist as individual polypeptides. Notice that each hasan e)(\racellular ligand-binding site. an Cl helix spanning themembrane, and an intracellular tail containing multiple tyrosines,

e The binding of a signaling molecule (such as a growth fador) causestwo receptor polypeptides to associate closely with each other,forming a dimer (dimerization),

("

6$Activated tyrosinekinase regions(unphosphorylateddimer)

"l,)6ADP

Fully activated receptortyrosine kinase(phosphorylateddimer)

-Activated relayproteins

Cellularresponse 1

Cellularresponse 2

Inactiverelay proteins "l.wI

€) Dimerization adivates the tyrosine kinase region of eachpolypeptide; each tyrosine kinase adds a phosphate from an ATPmolecule to a tyrosine on the tail of the other polypeptide,

o Now that the receptor protein is fully adivated. it is recognized byspecific relay proteins inside the cell. Each such protein binds to aspecific phosphorylated tyrosine. undergoing a resulting structuralchange that activates the bound protein. Each adivated proteintriggers a transdudion pathway, leading to a cellular response.


Ion Channel Receptors

A Iiga.nd-gated ion (;hannel is a type of membrane receptor

containing a region that can act as a "gate" when the receptor

changes shape. \Vhen a signaling molecule binds as a ligand tothe receptor protein, the gate opens or closes, allowing or

blocking the flow of specific ions, such as Na+ or Ca2+, through

a channel in the receptor. Like the other receptors we have

discussed, these proteins bind the ligand at a specific site on theirextracellular sides,

protein, activating it (Figure 11.8). With the hormoneattached, the active form of the receptor protein then entersthe nucleus and turns on specific genes that control male sexcharacteristics.

How does the activated hormone-re<eptor complex turnon genes? Recall that the genes in a cell's DNA function by being transcribed and processed into messenger RNA (mRNA),which leaves the nucleus and is translated into a specific protein by ribosomes in the cytoplasm (see Figure 5.26). Specialproteins called transcription factors control which genes areturned on-that is, which genes are transcribed into mRNAin a particular cell at a particular time. The testosterone receptor, when activated, acts as a transcription factor that turns onspecific genes.

By acting as a transcription factor, the testosterone receptoritself carries out the complete transduction of the signal. Mostother intracellular re<eptors function in the same way, althoughmany of them are already in the nucleus before the signalingmolecule reaches them (an example is the thyroid hormonereceptor). Interestingly, many of these intracellular receptorproteins are structurally similar, suggesting an evolutionaryPlasmal

membraneligand-gatedion channel receptor

Slgnalin~O GateQ 0' Q Q 0molecule closed Q Ions 0(ligand) \ .(1~.... 0 0

o Here we show aligand-gated ionchannel receptor inwhich the gateremains closeduntil a ligand bindsto the receptor.

EXTRACELLULARFLUID

f)Testosterone bindsI"!l------I to a receptor protein

in the cytoplasm,activating it.-"~'Hormone

receptorcomplex

-lOThe bound proteinacts as a transcriptionfactor, stimulating thetranscription ofthe gene into mRNA.

New protein

~;---10Th' mRNA;,translated into aspecific protein.

Hormone ---,--"I~(testosterone) OThe steroid

t--------:rl hormone testosteronepasses through theI plasma membrane.

.............. Plasma""" membraneReceptor

protein

CYTOPLASM

NUClEUS

... Figure 11.8 Steroid hormone interacting with anintracellular receptor.

D Why is a eel/-surface receptor protein not required for this steroidhormone to enter the cell?

mRNA \..----

oThe hormonereceptor complex

yl---- -------rl enters the nucleusand binds to specificgenes.

Cellularresponse

Gate closed00

o

o 0

o 0 Q""'"o 0_o Q Q .........

oo

Gate open 0f) When the ligandbinds to thereceptor and thegate opens, specificions can flowthrough the channeland rapidly changethe concentration ofthat particular ioninside the cell. Thischange may directlyaffect the activity ofthe cell in some way.

o When the liganddissociates from thisreceptor, the gatecloses and ions nolonger enter thecell.

Ligand-gated ion channels are very important in the nervoussystem. For example, the neurotransmitter molecules released ata synapse between two nerve cells {see Figure 11.5b) bind asligands to ion channels on the receiving cell, causing thechannels to open. Ions flow in (or, in some cases, out), triggeringan electrical signal that propagates down the length of thereceiving cell. Some gated ion channels are controlled byelectrical signals instead of ligands; these voltage-gated ionchannels are also crucial to the functioning of the nervoussystem, as we will discuss in Chapter 48.

CHAPTER HEV£~ Cell Communication 213

kinship. We will look more closely at hormones with intracellular receptors in Chapter 45.

CONCEPT CHECI( 11.Z

layed along a pathway, we mean that certain information ispassed on. At each step, the signal is transduced into a different form, commonly a shape change in a protein. Very often,the shape change is brought about by phosphorylation.

J. Nerve growth factor (NGF) is a water-soluble signaling molecule. Would you expect the receptor for NGFto be intracellular or in the plasma membrane? Why?

2. -:.rMiil. What would the effect be if a cell made

defective receptor tyrosine kinase proteins that wereunable to dimerize?

For suggested answers. see Appendix A

r;~:;s:;:~~~~Cascades ofmolecular interactions relaysignals from receptors to targetmolecules in the cell

When receptors fOT signaling molecules aTe plasma membrane proteins, like most of those we have discussed, the

transduction stage ofcell signaling is usually a multistep pathway. Steps often include activation of proteins by addition orremoval of phosphate groups, or release of other small molecules or ions that act as messengers. One benefit of multiplesteps is the possibility ofgreatly amplifying a signal. If some ofthe molecules in a pathway transmit the signal to numerousmolecules at the next step in the series, the result can be alarge number ofactivated molecules at the end of the pathway.Moreover, multistep pathways provide more opportunitiesfor coordination and regulation than simpleT systems do. Thisallows fine-tuning of the Tesponse, in both unicellular andmulticellular organisms, as we'll discuss later in the chapter.

Signal Transduction Pathways

The binding of a specific signaling molecule to a receptor inthe plasma membrane triggers the first step in the chain ofmolecular interactions-the signal transduction pathwaythat leads to a particular response within the celL Like fallingdominoes, the signal-activated receptor activates anothermolecule, which activates yet another molecule, and so on,

until the protein that produces the final cellular response is activated. The molecules that relay a signal from receptor to response, which we call relay molecules in this book, are oftenproteins. The interaction of proteins is a major theme of cellsignaling. Indeed, protein interaction is a unifying theme ofallregulation at the cellular level.

Keep in mind that the original signaling molecule is notphysically passed along a signaling pathway; in most cases, itnever even enters the cell. When we say that the signal is re-


Protein Phosphorylation andDephosphorylation

Previous chapters introduced the concept ofactivating a proteinby adding oneor more phosphate groups to it (see Figure 8.11a).In Figure 11.7, we have already seen how phosphorylation isinvolved in the activation of receptor tyrosine kinases. In fact,the phosphorylation and dephosphorylation of proteins is awidespread cellular mechanism for regulating protein activity.The general name for an enzyme that transfers phosphategroups from ATP to a protein is protein kinase. Recail that a

receptor tyrosine kinase phosphorylates tyrosines on theother receptor tyrosine kinase in a dimer. Most cytoplasmicprotein kinases, however, act on proteins different fromthemselves. Another distinction is that most cytoplasmicprotein kinases phosphorylate either the amino acid serine orthreonine, rather than tyrosine. Such serine/threonine kinases are widely involved in signaling pathways in animals,plants, and fungi.

Many ofthe relay molecules in signal transduction pathwaysare protein kinases, and they often act on other protein kinasesin the pathway. figure 11.9 depicts a hypothetical pathwaycontaining three different protein kinases that create a "phosphorylation cascade:' The sequence shown is similar to manyknown pathways, including those triggered in yeast by matingfactors and in animal cells by many growth factors. The signal

is transmitted by a cascade of protein phosphorylations, eachbringing with it a shape change. Each such shape change resultsfrom the interaction ofthe newly added phosphate groups withcharged or polar amino acids (see Figure 5.17). The addition ofphosphate groups often changes a protein from an inactiveform to an active form (although in other cases phosphorylation decreases the activity of the protein).

The importance of protein kinases can hardly be overstated. About 2% ofour own genes are thought to code for protein kinases. A single cell may have hundreds of differentkinds, each specific for a different substrate protein. Together,they probably regulate a large proportion of the thousands ofproteins in a cell. Among these are most of the proteins that,

in turn, regulate cell reproduction. Abnormal activity of sucha kinase can cause abnormal cell growth and contribute to thedevelopment of cancer.

Equally important in the phosphorylation cascade are theprotein phosphatases, enzymes that can rapidly remove phosphate groups from proteins, a process called dephosphorylation. By dephosphorylating and thus inactivating proteinkinases, phosphatases provide the mechanism for turning offthe signal transduction pathway when the initial signal is no

Cellularresponse

oFinally, active proteinkinase 3 phosphorylates aprotein (pink) that bringsabout the cell's response tothe signal.

AD'

Inactiveprotein

", pp®,

oA relay moleculeacti~ates protein kinase 1.

Adi~ated relaymolecule

Signaling molecule

Receptor

o Enzymes called proteinphosphatases (PP)catalyze the removal ofthe phosphate groupsfrom the proteins,making them inactiveand available for reuse.

E)Active protein kinase 1transfers a phosphate from AlPto an inacti~e molecule of

kinase protein kinase 2, thus activating

p'o~~:~t;~~ th" "'''d k"",

2 ~ AOP~, ) oActive protem kinase 2

then catalyzes the phos-II ~~.~. •• •• phorylatlon (and activation) of

®, protein kinase 3

... Figure 11.9 A phosphorylation cascade. In a phosphorylation cascade, aseries of differentmolecules in a pathway are phosphorylated in turn, each molecule adding a phosphate group to thenext one In line. In thiS example. phosphorylation adi~ates each molecule. and dephosphorylationreturns it to Its Inadi~e form The adi~e and inactIVe forms of each protein are represented bydifferent shapes to remind you that adivation is usually associated with achange in molecular shape.

D Which protein is responsible foractivation of protem kinase 3?

longer present. Phosphatases also make the protein kinasesavailable for reuse, enabling the cell to respond again to an extracellular signal. At any given moment, the activity ofa protein regulated by phosphorylation depends on the balance inthe cell between active kinase molecules and active phosphatase molecules. The phosphorylation/dephosphorylationsystem acts as a molecular switch in the cell, turning activitieson or off as required.

Small Molecules and Ions as SecondMessengers

Not all components of signal transduction pathways are proteins. Many signaling pathways also involve small, nonprotein,

water-soluble molecules or ions called second messengers.(The extracellular signaling molecule that binds to the membrane receptor is a pathway's "first messenger.") Because sec·ond messengers are both small and wateHoluble, they canreadily spread throughout the cell by diffusion. For example, aswe'll see shortly, it is a second messenger called cyclic AMPthat carries the signal initiated by epinephrine from the plasmamembrane ofa liver or muscle cell into the cell's interior, whereit brings about glycogen breakdown. Second messengers participate in pathways initiated by both G protein-coupled receptors and receptor tyrosine kinases. The two most widely usedsecond messengers are cyclic AMP and calcium ions, Ca'H. Alarge variety of relay proteins are sensitive to the cytosolic concentration ofone or the other ofthese second messengers.


oool):>-o-~-o-~-o-~-o-c8 Adenylylcyclase

I I I 2 "' ..0-0-0- 0 t

Pyrophosphate

®-®,OH OH

Phosphodiesterase

o l):>.. -O-~-O-IH~' a I0q

OH OH

AMP

.. Figure 11.10 Cyclic AMP. The second messenger cyclic AMP (cAMP) is made from AlP byadenylyl cyclase, an enzyme embedded in the plasma membrane. Cyclic AMP is inactivated byphosphodiesterase, an enzyme that converts it to AMP.'Wili• What would happen if a molecule rhar inactivared phosphodiesterase wereintroduced inro the celP

Cellular responses

... Figure 11.11 cAMP as a second messenger in aG-protein-signaling pathway. The first messenger activates aGprotein·coupled receptor. which activates a specific G protein, Inturn, the G protein activates adenylyl cyclase. which catalyzes theconversion of ATP to cAMP, The cAMP then acts as a secondmessenger and activates another protein, usually protein kinase A.leading to cellular responses,

Further regulation of cell metabolism is provided by otherG-protein systems that inhibit adenylyl cyclase. In these systems, a different signaling molecule activates a different receptor, which activates an inhibitory G protein.

Now that we know about the role of cAMP in G-proteinsignaling pathways, we can explain in molecular detail howcertain microbes cause disease. Consider cholera, a disease

Adenylylcyclase

-Gprotem

~First messenger(Signaling mole{Ulesuch as epinephrine)

~

Gprotein-coupledreceptor

Cyclic AMP

Once Earl Sutherland had established that epinephrine somehow causes glycogen breakdown without passing through theplasma membrane, the search began for what he later named

the second messenger that transmits the signal from the plasma

membrane to the metabolic machinery in the cytoplasm.Sutherland found that the binding of epinephrine to the

plasma membrane of a liver cell elevates the cytosolic concen~

tration of a compound called cyclic adenosine monophos~

phate, abbreviated cyclic AMP or cAMP (Figure 11.10). Anenzyme embedded in the plasma membrane, adenylyl

cyclase, converts ATP to cAMP in response to an extracellu·lar signal-in this case, epinephrine. But epinephrine doesn't

stimulate adenylyl cyclase directly. When epinephrine outsidethe cell binds to a specific receptor protein, the protein activates adenylyl cyclase, which in turn can catalyze the synthesis of many molecules of cAMP. In this way, the normalcellular concentration of cAMP can be boosted 2o-fold in amatter of seconds. The cAMP broadcasts the signal to the cytoplasm. It does not persist for long in the absence of the hormone because another enzyme, called phosphodiesterase,converts cAMP to AMP. Another surge of epinephrine isneeded to boost the cytosolic concentration of cAMP again.

Subsequent research has revealed that epinephrine isonly one of many hormones and other signaling moleculesthat trigger the formation of cAMP. It has also brought tolight the other components of cAMP pathways, includingG proteins, G protein-coupled receptors, and protein kinases (Figure 11.11). The immediate effect of cAMP is

usually the activation of a serine/threonine kinase calledprotein kinase A. The activated kinase then phosphorylates various other proteins, depending on the cell type.(The complete pathway for epinephrine's stimulation ofglycogen breakdown is shown later, in Figure 11.15.)


... Figure 11.12 The maintenance of calcium ionconcentrations in an animal cell. The Cal+ concentration in thecytosol is usually much lower (light blue) than that in the extracellularfluid and ER (darker blue). Protein pumps 10 the plasma membrane andthe ER membrane. driven by AT~ move CaH from the cytosol into theextracellular fluid and into the lumen of the ER. Mitochondrial pumps.driven by chemiosmosis (see Chapter 9), move Cal+ into mitochondriawhen the calcium level in the cytosol rises significantly.

the blood and extracellular fluid of an animal often exceeds

that in the cytosol by more than 10,000 times. Calcium ions

are actively transported out of the cell and are actively im

ported from the cytosol into the endoplasmic reticulum

(and, under some conditions, into mitochondria and chloro

plasts) by various protein pumps (see Figure 11.12). As a re

sult, the calcium concentration in the ER is usually much

higher than that in the cytosol. Because the cytosolic calcium

level is low, a small change in absolute numbers of ions rep

resents a relatively large percentage change in calcium con

centration.

In response to a signal relayed by a signal transduction

pathway, the cytosolic calcium level may rise, usually by a

mechanism that releases Ca2+ from the cell's ER. The path

ways leading to calcium release involve still other second

messengers, inositol trisphosphate (IP3) and diacylglycerol

(DAG). These two messengers are produced by cleavage of a

certain kind of phospholipid in the plasma membrane.

Ca2+pump

'- Endoplasmicreticulum (ER)

Plasma/membrane

Nucleus

~_ ",1"'-"Ca2+

~ pump

Mitochondrion"

::tt,-C,'.~T"\.pump

K,y

CYTOSOl

EXTRACELLULARFlUID

• High lCa2+1Low [Cal+l

Calcium Ions and Inositol Trisphosphate (lP:J

that is frequently epidemic in places where the water supply is

contaminated with human feces. People acquire the cholera

bacterium, Vibrio cholerae, by drinking contaminated water.

The bacteria colonize the lining ofthe small intestine and pro

duce a toxin. The cholera toxin is an enzyme that chemically

modifies a G protein involved in regulating salt and water se

cretion. Because the modified G protein is unable to hydrolyzeGTP to GDP, it remains stuck in its active form, continuously

stimulating adenylyl cyclase to make cAMP. TIle resulting

high concentration of cAMP causes the intestinal cells to se

crete large amounts of salts, with water following by osmosis,

into the intestines. An infected person quickly develops pro

fuse diarrhea and if left untreated can soon die from the loss

of water and salts.

Our understanding of signaling pathways involving cyclic

AMP or related messengers has allowed us to develop treat

ments for certain conditions in humans. In one pathway

cye/ic GAfP, or cGMP, acts as a signaling molecule whose ef

fects include relaxation ofsmooth muscle cells in artery walls.

A compound that inhibits the hydrolysis of cGMP to GMP,

thus prolonging the signal, was originally prescribed for chest

pains because it increased blood flow to the heart muscle.

Under the trade name Viagra (see Figure ILl), this com

pound is now widely used as a treatment for erectile dysfunc

tion in human males. Because Viagra leads to dilation of

blood vessels, it also allows increased blood flow to the penis,

optimizing physiological conditions for penile erections. The

similarities between external reproductive structures in

males and females (see Chapter 46) have motivated medical

researchers to initiate clinical studies exploring whether Via

gra might also be used to treat sexual dysfunction in females;

these studies are currently under way.

Many signaling molecules in animals, including neurotransmitters, growth factors, and some hormones, induce re

sponses in their target cells via signal transduction pathways

that increase the cytosolic concentration of calcium ions

(CaH). Calcium is even more widely used than cAMP as a

second messenger. Increasing the cytosolic concentration of

Ca2+ causes many responses in animal cells, including muscle

cell contraction, secretion of certain substances, and cell divi

sion. In plant cells, a wide range of hormonal and environ

mental stimuli can cause brief increases in cytosolic CaH

concentration, triggering various signaling pathways, such as

the pathway for greening in response to light (see Figure 39.4).

Cells use CaH as a second messenger in both G-protein and

receptor tyrosine kinase pathways.

Although cells always contain some CaH, this ion can

function as a second messenger because its concentration in

the cytosol is normally much lower than the concentration

outside the cell {Figure 11.12}. In fact, the level ofCaH in


IP3-gatedcalcium channel

<II Figure 11.13 Calcium and 1P3 insignaling pathways. Calcium ions (Ca2 +)and inositol trisphosphate (IP3) function assecond messengers in many signaltransduction pathways. In this figure, theprocess is initiated by the binding of asignalingmolecule to aG protein-coupled receptor. Areceptor tyrosine kinase could also initiate thispathway by activating phospholipase C

ODAG functions asa second messengerin other pathways,

1a_D~G

PIP, ""§o",

(second messenger)

80./----~

o 0 Vano~s / Cellularo 0 0 ---+- pro.tems ---+- responses

o 0 0 actlv~ated""Ca2+

(secondmessenger)

~----"~-0Calcium ions flow out of 0The calcium ionsthe ER (down their con- activate the nextcentration gradient), raising protein in one or morethe Ca2+ level in the cytosol. signaling pathways.

e Phospholipase Ccleaves aplasma membrane phospholipidcalled PlP2 into DAG and IP3,

-"""......-/Phospholipase C

Signaling molecule(first messenger)

oo 0

Ca2+

G protein-coupledreceptor

/CYTOSOL

EXTRACELLULARFLUID

Endoplasmicreticulum (ER)

o IP3quickly diffuses throughthe cytosol and binds to an IP3gated calcium channel in the ERmembrane, causing it to open.

OA signaling molecule bindsto a receptor, leading toactivation of phospholipase C

Figure 11.13 shows how this occurs and how IP3 stimulates therelease ofcalcium from the ER. Because IP3 acts before calciumin these pathways, calcium could be considered a ~third messenger.' However, scientists use the term second messenger for allsmall, nonprotein components ofsignal transduction pathways.

1. \Vhat is a protein kinase, and what is its role in asignal transduction pathway?

2. When a signal transduction pathway involves a phosphorylation cascade, how does the cell's response getturned off?

3. What is the actual ~signal" that is being transduced inany signal transduction pathway, such as those shown inFigures 11.6 and 11.9? In other words, in what way is information being passed from the exterior to the interioroftheceU?

4, -'W'UiM Upon activation of phospholipase C byligand binding to a receptor, what effect does the IPrgated calcium channel have on Ca2+ concentration inthe cytosol?

For suggested answers. see Appendix A

CONCEPT CHECK 11.3

r::;;:~7e~~~~ signaling leads toregulation of transcription orcytoplasmic activities

We now take a closer look at the cell's subsequent response toan extracellular signal-what some researchers call the "output response~ \'(fhat is the nature of the final step in a signaling pathway?

Nuclear and Cytoplasmic Responses

Ultimately, a signal transduction pathway leads to theregulation ofone or more cellular activities. The responseat the end ofthe pathway may occur in the nucleus of thecell or in the cytoplasm.

Many signaling pathways ultimately regulate protein synthesis, usually by turning specific genes on or off in the nucleus. Like an activated steroid receptor (see Figure 11.8), thefinal activated molecule in a signaling pathway may functionas a transcription factor. Figure 11.14 shows an example inwhich a signaling pathway activates a transcription factor


... Figure 11.14 Nuclear responses to a signal: theactivation of a specific gene by a growth factor. Thisdiagram is a simplified representation of a typical signalingpathway that leads to the regulation of gene activity in the cellnucleus. The initial signaling molecule, a local regulator called agrowth factor. triggers a phosphorylation cascade. (The ATPmolecules that serve as sources of phosphate are not shown.) Oncephosphorylated. the last kinase in the sequence enters the nucleusand there activates a gene-regulating protem, a transcriptionfactor This protein stimulates a speCific gene so that an mRNA issynthesized. which then directs the synthesis of a particular proteinin the cytoplasm.

Reception ~

Binding of epinephrine to Gprotein-coupled receptor (1 molecule)

t

... Figure 11.15 Cytoplasmic response to a signal: thestimulation of glycogen breakdown by epinephrine. In thissignaling system, the hormone epinephrine acts through a Gproteincoupled receptor to activate a succession of relay molecules, includingcAMP and two protein kinases (see also Figure 11 11), The final proteinto be activated is the enzyme glycogen phosphorylase, which usesinorganic phosphate to release glucose monomers from glycogen in theform of glucose-I-phosphate molecules. This pathway amplifies thehormonal signal. because one receptor protein can activate about 100molecules of Gprotein, and each enzyme in the pathway, once activated.can act on many molecules of its substrate. the neKl molecule in thecascade. The number of activated molecules given for each step isapproximate,

IResponse I

ITransduction I~Inactive G protein t

Active Gprotem (102molecules)

Inactive adenylyl cyOActive adenylyl cyclase (1 02)

AnCyclic AMP (104)

Inactive protem kina~Active protem kinase A(104)

Inactive phosphorylaseQActive phosphorylase kinase (10s)

Inactive glycogen PhosPhorylC).Active glycogen phosphorylase (1 06)

GIYC~Glucose-l-phosphate

(108molecules)

Response

I Reception I

,Gene

I Transduction 1

Growth factor

mRNA

Ad,,, -...:.,.transcription, ,factor

InactivetransCflptlonfactor

DNA

NUCLEUS

CYTOPLASM

that turns a gene on: The response to the growth factor signal is the synthesis of mRNA, which will be translated in thecytoplasm into a specific protein. In other cases, the transcription factor might regulate a gene by turning it off. Oftena transcription factor regulates several different genes.

Sometimes a signaling pathway may regulate the activity ofproteins rather than their synthesis, directly affecting proteinsthat function outside the nucleus. For example, a signal maycause the opening or closing of an ion channel in the plasmamembrane or a change in cell metabolism. As we have discussed already, the response of liver cells to signaling by thehormone epinephrine helps regulate cellular energy metabolism by affecting the activity ofan enzyme. The final step in thesignaling pathway that begins with epinephrine binding acti-

vates the enzyme that catalyzes the breakdown of glycogen.Figure 11.15 shows the complete pathway leading to the release of glucose-I-phosphate molecules from glycogen. Notethat as each molecule is activated, the response is amplified, aswe will discuss later.

In addition to the regulation of enzymes, signalingevents may also affect other cellular attributes, such asoverall cell shape. An example of this regulation can befound in the activities leading to the mating of yeast cells(see Figure 11.2). Yeast cells are not motile; their matingprocess depends on the growth of localized projections inone cell toward a cell of the opposite mating type. As shown


in Figure 11.16, binding of the mating factor causes this directional growth. \xrhen the mating factor binds, it activatessignaling-pathway kinases that affect the orientation of growthof cytoskeletal microfilaments. Because activation of signaling

kinases is coupled in this way to cytoskeletal dynamics, cell pro

jections emerge from regions ofthe plasma membrane exposedto the highest concentration of the mating factor. As a result,these projections are oriented toward the cell of the oppositemating type, which is the source of the signaling molecule.

The signal receptors, relay molecules, and second messengers introduced so far in this chapter participate in avariety of pathways, leading to both nuclear and cytoplasmic responses. Some of these pathways lead to cell divi

sion. The molecular messengers that initiate cell-division

pathways include growth factors and certain plant and an·imal hormones. Malfunctioning of growth factor path·ways like the one in Figure 11.14 can contribute to thedevelopment of cancer, as we will see in Chapter 18.

". ' "In uiHow do signals induce directional cell growth in yeast?

EXPERIMENT When ayeast cell binds mating factor molecules from a cell of the opposite mating type, asignal-ing pathway causes it to grow a projection toward the potential mate. The cell with the projection is called a"shmoo" because it resembles a 19505 cartoon character by that name. Dina Matheos and colleagues in Mark Rose'slab at Princeton Umversity sought to determine how mating factor signaling IS linked to this asymmetrical growthPrevious work had shown that activation of one of the kinases in the signaling cascade (Fus3) caused it to move tothe membrane near where the factor bound. Preliminary experiments by these researchers identified formin, a protein that directs the construction of microfilaments, as a phosphorylation target of Fus3 kinase, To examine the roleof Fus3 and formin in shmoo formation, the researchers generated two mutant yeast strains: one that no longer hadthe kinase (thiS strain IS called <lFus3) and one that lacked the formin (Mormin) To observe the effects of these mutations on cell growth induced by the mating factor. the cell walls of each strain were first stained with agreen fluorescent dye. These green-stained cells were then exposed to mating factor and stained with a red fluorescent dye thatlabeled new cell wall growth, Images taken of the cells after the staining procedure were then compared with a similarly treated strain that expressed Fus3 and formin (the wild type),

RESULTS The cells of the wild-type strain showed shmooprojections, whose walls were stained red, while the rest of theircell walls were green, indicating asymmetrical growth, Cells of boththe <lFus3 and Mormin strains showed no shmoo formation, andtheir cell walls were stained almost uniformly yellow, This color resulted from merged green and red stains, indicating symmetricalgrowth, characteristic of cells not exposed to mating factor.

() Phosphorylation cascadeactivates Fus3, which movesto plasma membrane.

FOlmin

1'"

---Actinsubunit

aformin

-Microfilament•

aFormin initiates growth ofmicrofilaments that formthe shmoo prOJections.

Shmoo prOjectionforming - _

D.Fus3

OFus3 phosphorylatesformlll,activating it.

\!'hOSphory., laMn~(aSCade

~

Wild-type (shmoos)

GMatlllgfactoractivatesreceptor

f)G protein binds GTPand becomes activated,

Fus3

CONCLUSiON The similar defect (lack of ability toform shmoos) in strainslacking either Fus3 orformin suggests that bothproteins are required forshmoo formation, Theseresults led the investigatorsto propose the modelshown here for the induction of directed asymmetrical growth in the receivingcell toward the cell of theopposite mating type.

SOURCE 0, Mathe<ls et ai, Pheromone-induced polarizanoo is de,.e'ldent on the Fus3p MAPK acting through the forminBm1p. .ioor~/ of eel/Biology 1659g-109 (10041

-m',iliA Based on these results and the proposed model from this work, what would happen to acell if itsFus3 kinase were not able to associate with the membrane upon activation?


... Figure 11.17 The specificity of cell signaling. The particularproteins acell possesses determirle what slgrlaling molecules it respoods toand the rlature of the respoose. The four cells irl these diagrams resp()rld tothe same signaling molecule (red) in different ways because each has adifferent set of proteins (purple and teal shapes). Note, howev€l", that thesame kinds of molecules can participate in more than one pathway.

Response 3

Response 5

Cell D. Different receptorleads to a different response.

Cell B. Pathway branches.leading to two responses.

Response 2

h"ooor inhibition

Relaymolecules

Response 1

Cell A. Pathway leadsto asingle response.

Cell C. Cross-talk occursbetween two pathways.

Response 4

Signalingmolecule

Receptor

Thus, two cells that respond differently to the same signaldiffer in one or more of the proteins that handle and respondto the signal. Notice in Figure 1Ll7 that different pathwaysmay have some molecules in common. For example, cells A, B,and C all use the same receptor protein for the red signalingmolecule; differences in other proteins account for their differing responses. In cell 0, a different receptor protein is usedfor the same signaling molecule, leading to yet another response. In cell B, a pathway that is triggered by a single kind ofsignal diverges to produce two responses; such branched

Fine-Tuning of the Response

The Specificity of Cell Signaling andCoordination of the Response

Consider two different cells in your body-a liver cell and aheart muscle cell, for example. Both are in contact with yourbloodstream and are therefore constantly exposed to manydifferent hormone molecules, as well as to local regulators secreted by nearby cells. Yet the liver cell responds to some signals but ignores others, and the same is true for the heart cell.And some kinds ofsignals trigger responses in both cells-butdifferent responses. For instance, epinephrine stimulates theliver cell to break down glycogen, but the main response oftheheart cell to epinephrine is contraction, leading to a morerapid heartbeat. How do we account for this difference?

TIle explanation for the specificity exhibited in cellular responses to signals is the same as the basic explanation for virtuallyall differences between cells: Different kinds ofcells have differentcollections ofproteins (Figure 11.17). (This is because differentkinds of cells turn on different sets of genes.) TIle response of aparticular cell to a signal depends on its particular collection ofsignal receptor proteins, relay proteins, and proteins needed tocarry out the response. A liver cell, for example, is poised to respond appropriately to epinephrine by having the proteins listedin Figure 11.15 as well as those needed to manufacture glycogen.

Signal Amplification

Elaborate enzyme cascades amplify the cell's response to a signal. At each catalytic step in the cascade, the number of activated products is much greater than in the preceding step. Forexample, in the epinephrine-triggered pathway in Figure 1LIS,each adenylyl cyclase molecule catalyzes the formation ofmany cAMP molecules, each molecule of protein kinase Aphosphorylates many molecules ofthe next kinase in the pathway, and so on. The amplification effect stems from the factthat these proteins persist in the active form long enough toprocess numerous molecules of substrate before they becomeinactive again. As a result of the signal's amplification, a smallnumber ofepinephrine molecules binding to receptors on thesurface of a liver cell or muscle cell can lead to the release ofhundreds of millions ofglucose molecules from glycogen.

Regardless ofwhether the response occurs in the nucleus or inthe cytoplasm, it is fine-tuned at multiple points. As mentioned earlier, signaling pathways with numerous steps between asignaling event at the cell surface and the cell's responsehave two important benefits: They amplify the signal (and thusthe response), and they provide different points at which a cell'sresponse can be regulated. This allows coordination ofsignaling pathways and also contributes to the specificity of the response. The overall efficiency of the response is also enhancedby scaffolding proteins. Finally, a crucial point in fine-tuningthe response is the termination of the signaL


... Figure 11.18 A scaffolding protein. The scaffolding protemshown here (pink) simultaneously binds to aspecific acti~ated

membrane receptor and three different protein kinases. This physicalarrangement facilitates signal transduction by these molecules.

pathways often involve receptor tyrosine kinases (which canactivate multiple relay proteins) or second messengers (whichcan regulate numerous proteins). In cell C, two pathways trig~

gered by separate signals converge to modulate a single re

sponse. Branching of pathways and "cross-talk" (interaction)

bet..."een pathways are important in regulating and coordinat·ing a cell's responses to information coming in from differentsources in the body. (You'll learn more about this coordinationlater, in the next section.) Moreover, the use of some of the

same proteins in more than one pathway allows the cell toeconomize on the number of different proteins it must make.

Signaling Efficiency: Scaffolding Proteins andSignaling Complexes

The signaling pathways in Figure 11.17 (as well as some of theother pathway depictions in this chapter) are greatly simplified. The diagrams show only a few relay molecules and, forclarity's sake, display these molecules spread out in the cytosol. If this were true in the cell, signaling pathways wouldoperate very inefficiently because most relay molecules areproteins, and proteins are too large to diffuse quickly throughthe viscous cytosol. How does a particular protein kinase, forinstance, find its substrate?

Recent research suggests that the efficiency of signal trans·duction may in many cases be increased by the presence ofscaffolding proteins, large relay proteins to which severalother relay proteins are simultaneously attached. For example,one scaffolding protein isolated from mouse brain cells holdsthree protein kinases and carries these kinases with it when itbinds to an appropriately activated membrane receptor; it thusfacilitates a specific phosphorylation cascade (Figure 11.18). Infact, researchers are finding scaffolding proteins in brain cellsthat permanently hold together networks of signaling-pathwayproteins at synapses. This hardwiring enhances the speed and

accuracy of signal transfer betv"een cells, because the rate ofprotein-protein interaction is not limited by diffusion.

\Vhen signaling pathways were first discovered, they werethought to be linear, independent pathways. Our understand

ing of the processes of cellular communication has benefitedfrom the realization that things are not that simple. In fact, asseen in Figure 11.17, some proteins may participate in morethan one pathway, either in different cell types or in the samecell at different times or under different conditions. This viewunderscores the importance of permanent or transient protein complexes in the functioning of a cell.

The importance of the relay proteins that serve as pointsof branching or intersection in signaling pathways is highlighted by the problems arising when these proteins are defective or missing. For instance, in an inherited disordercalled \\fiskou-Aldrich syndrome (WAS), the absence of a

single relay protein leads to such diverse effects as abnormalbleeding, eczema, and a predisposition to infections andleukemia. These symptoms are thought to arise primarilyfrom the absence of the protein in cells of the immune system. By studying normal cells, scientists found that theWAS protein is located just beneath the cell surface. Theprotein interacts both with microfilaments of the cytoskeleton and with several different components of signalingpathways that relay information from the cell surface, including pathways regulating immune cell proliferation. Thismultifunctional relay protein is thus both a branch pointand an important intersection point in a complex signaltransduction network that controls immune cell behavior.

When the WAS protein is absent, the cytoskeleton is notproperly organized and signaling pathways are disrupted,leading to the WAS symptoms.

Termination of the Signal

To keep Figure 11.17 simple, we did not indicate theinactivation mechanisms that are an essential aspect of cellsignaling. For a cell of a multicellular organism to remainalert and capable of responding to incoming signals, eachmolecular change in its signaling pathways must last only ashort time. As we saw in the cholera example, if a signalingpathway component becomes locked into one state,whether active or inactive, the consequences for the organ

ism can be dire.Thus, a key to a cell's continuing receptiveness to regula·

tion by signaling is the reversibility of the changes that sig·nals produce. The binding of signaling molecules toreceptors is reversible; the lower the concentration of signaling molecules is, the fewer will be bound at any givenmoment. When signaling molecules leave the receptor, thereceptor reverts to its inactive form. Then, by a variety ofmeans, the relay molecules return to their inactive forms:

Threedifferentproteinkinases

Plasmamembrane

I

Scaffoldingprotein

Receptor

Signalingmolecule


The GTPase activity intrinsic to a G protein hydrolyzes itsbound GTP; the enzyme phosphodiesterase converts cAMPto AMP; protein phosphatases inactivate phosphorylatedkinases and other proteins; and so forth. As a result, the cell

is soon ready to respond to a fresh signal.

In this section, we explored the complexity of signaling initiation and termination in a single pathway, and we saw thepotential for pathways to intersect with each other. In the nextsection, we'll consider an important network of interacting

pathways in the cell.

used in a classic Greek poem to refer to leaves falling from atree). During this process, cellular agents chop up the DNAand fragment the organelles and other cytoplasmic components. The cell shrinks and becomes lobed (called "bleb

bing~) (Figure 11.19), and the cell's parts are packaged upin vesicles that are engulfed and digested by specialized

scavenger cells, leaving no trace. Apoptosis protects neighboring cells from damage that they would otherwise sufferif a dying cell merely leaked out all its contents, including itsmany digestive and other enzymes.

One of the most elaborate networks of signaling pathways inthe cell seems to ask and answer the basic question posed by

Hamlet: To be or not to be? Cells that are infected or damaged or that have simply reached the end of their functionallife span often enter a program of controlled cell suicidecalled apoptosis {from the Greek, meaning "falling off;' and

r~;:;t::i:~~grammed celldeath) integrates multiple cellsignaling pathways

1. How can a target cell's response to a hormone be am~plified more than a millionfold?

2. -'mt,,14 If two cells have different scaffolding

proteins, explain how they could behave differently inresponse to the same signaling molecule.

For suggested answers, see Appendix A.

CONCEPT CHECK 11.4 Apoplosis in the Soil Worm Caenorhabditise/egansEmbryonic development is a period during which apoptosis iswidespread and plays a crucial role. The molecular me<ha

nisms underlying apoptosis were worked out in detail by researchers studying embryonic development of a small soilworm, a nematode called Caenorhabditis elegans. Because theadult worm has only about a thousand cells, the researcherswere able to work out the entire ancestry of each cell. Thetimely suicide of cells occurs exactly 131 times during normaldevelopment of C. elegans, at precisely the same points in thecell lineage of each worm. In worms and other species, apoptosis is triggered by signals that activate a cascade of"suicide"proteins in the cells destined to die.

Genetic research on C. elegans has revealed two keyapoptosis genes, called ced-3 and ced-4 (ced stands for "cell death~),

which encode proteins essential for apoptosis. (The proteinsare called Ced-3 and Ced-4, respectively.) These and most

other proteins involved in apoptosis are continually presentin cells, but in inactive form; thus, protein activity is regu

lated rather than protein synthesis (by way of gene activity).

.. Figure 11.19 Apoptosis of a humanwhite blood cell. We can compare a normalwhite blood cell (left) with awhite blood cellundergoing apoptosis (right). The apoptotic cell isshrinking and forming lobes ("blebs"), whicheventually are shed as membrane-bounded cellfragments (colorized SEMs).

C~APTE~ ELEVEN Cell Communication 223

(a) No death signal. As long as Ced-9, located in the outermitochondrial membrane, is active, apoptosis is inhibited, andthe cell remains alive.

teases of apoptosis are called caspases; in the nematode, thechief caspase is Ced-3.

Apoptotic Pathways and the Signals ThatTrigger ThemIn humans and other mammals, several different pathways, in

volving about 15 different caspases, can carry out apoptosis.The pathway that is used depends on the type ofcell and on theparticular signal that triggers apoptosis. One major pathway involves mitochondrial proteins. Apoptotic proteins can formmolecular pores in the mitochondrial outer membrane, causingit to leak and release proteins that promote apoptosis. Surprisingly, these include cytochrome c, which functions in mitochondrial electron transport in healthy cells (see Figure 9.16)but acts as a cell death factor when released from mitochondria. The process of mitochondrial apoptosis in mammalsuses proteins similar to the nematode proteins Ced-3, Ced-4,and Ced-9.

At key points in the apoptotic program, proteins integratesignals from several different sources and can send a cell downan apoptotic pathway. Often, the signal originates outside thecell, like the death-signaling molecule depicted in Figure 11.20,which presumably was released by a neighboring cell. Whena death-signaling ligand occupies a cell-surface receptor, thisbinding leads to activation of caspases and other enzymes thatcarry out apoptosis, without involving the mitochondrialpathway. Two other types of alarm signals originate frominside the cell. One comes from the nucleus, generated whenthe DNA has suffered irreparable damage, and a second

comes from the endoplasmic reticulum when excessive protein misfolding occurs. Mammalian cells make Iife-or-death~decisions~ by somehow integrating the death signals and life

signals they receive from these external and internal sources.A built-in cell suicide mechanism is essential to develop

ment and maintenance in all animals. The similarities betweenapoptosis genes in nematodes and mammals, as well as the observation that apoptosis occurs in multicellular fungi and evenin single-celled yeasts, indicate that the basic mechanismevolved early in animal evolution. In vertebrates, apoptosis isessential for normal development of the nervous system, fornormal operation of the immune system, and for normal morphogenesis of hands and feet in humans and paws in othermammals (figure 11.21). A lower level of apoptosis in devel

oping limbs accounts for the webbed feet of ducks and otherwater birds, in contrast to chickens and other land birds with

nonwebbed feet. In the case of humans, the failure of appropriate apoptosis can result in webbed fingers and toes.

Significant evidence points to the involvement of apoptosisin certain degenerative diseases ofthe nervous system, such asParkinson's disease and Alzheimer's disease. Also, cancer canresult from a failure of cell suicide; some cases of humanmelanoma, for example, have been linked to faulty forms of

Cell~forms

blebs

Nucleases

Otherproteases

WUI:..I

MitochondrionI

Activationcascade

Ced-9protein (active)inhibits Ced-4activity

Ced-4 Ced-3'------v-------Inactive proteins

Ced-9(inactive)

Receptorfor deathsignalingmolecule

Deathsignalingmolecule

II.,

(b) Death signal. When a cell receives a death signal, Ced·9 isinactivated, relieving its inhibition of Ced·3 and Ced-4. ActiveCed-3, a protease, triggers a cascade of reactions leading toactivation of nucleases and other proteases_ The action of theseenzymes causes the changes seen in apoptotlC cells and eventualcell death.

In C. elegans, a protein in the outer mitochondrial membrane,called Ced-9 (the product of the ced-9 gene), serves as a mas

ter regulator of apoptosis, acting as a brake in the absence of asignal promoting apoptosis (figure 11.20). When a death signal is received by the cell, it overrides the brake, and the apoptotic pathway activates proteases and nucleases, enzymesthat cut up the proteins and DNA of the cell. The main pro-

... Figure 11.20 Molecular basis of apoptosis in C. elegans.Three proteins, Ced-l Ced-4. and Ced-9, are critical to apoptosis andits regulation in the nematode. ApoptoSis is more complicated inmammals but involves proteins similar to those in the nematode.


Interdigital tissue,

1=:;

1mm

,. .. ~"

... Figure 11.21 Effect of apoptosisduring paw development in themouse. In mice, humans, and other mammals,as well as in land birds, the embryonic regionthat develops into feet or hands initially has a

solid, platelike structure, Apoptosis eliminatesthe cells in the interdigital regions, thus formingthe digits, The embryonic mouse paws shownin these fluorescence light micrographs arestained so that cells undergoing apoptosis

appear bright yellow. Apoptosis of cells beginsat the margin of each interdigital region (left),peaks as the tissue in these regions is reduced(middle). and is no longer visible when theinterdigitaltissue has been eliminated (right).

For suggested answers, see AppendiK A.

1. Give an example of apoptosis during embryonic development, and explain its function in the developing

embryo.2. _',i@"IHl What type of protein defects could re

sult in apoptosis occurring when it should not? Whattype could result in apoptosis not occurring when itshould?

the human version of the C. e/egans Ced-4 protein. It is notsurprising, therefore, that the signaling pathways feeding into

apoptosis are quite elaborate. After all, the life-or-death question is the most fundamental one imaginable for a cell.

This chapter has introduced you to many of the generalmechanisms of cen communication, such as ligand binding,protein-protein interactions and shape changes, cascades ofinteractions, and protein phosphorylation. As you continuethrough the text, you will encounter numerous examples ofcell signaling.

CONCEPT CHECK 11.5

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I0 Reception I I0 Transduction I I0 Response I

SUMMARY OF KEY CONCEPTS

_',11'''''-11.1

Receptor

(..-.e.........

Relil'J' molecules

Activation.... of cellul~r

r'esponSl!

External signals are converted to responses within thecell (pp. 206-210)

.. Evolution of Cell Signaling Signaling in microbes has muchin common with processes in multicellular organisms, suggesting an early origin of signaling mechanisms. Bacterial cellscan sense the local density of bacterial cells (quorum sensing)by binding molecules secreted by other cells. In some cases,such signals lead to aggregation of these cells into biofilms.

.. local and long-Distance Signaling In local signaling, animal cells may communicate by direct contact or by secretinglocal regulators, such as growth factors or neurotransmitters.For signaling over long distances, both animals and plants usehormones; animals also signal along nerve cells.

.. The Three Stages of Cell Signaling: A Preview EarlSutherland discovered how the hormone epinephrine acts oncells, shown here as an example of a cell-signaling pathway:

As discussed in Sections 11.2 and 11.3, the signal is transmittedby successive shape changes in the receptor and relay molecules.

In'·estlgallon How Do CdlsCommunicate with E.ch Other?Acti,·ity Overview of Cell Signaling

•• ' 111"-11.2Reception: Asignaling molecule binds to a receptorprotein, causing it to change shape (pp. 210-214).. The binding between signaling molecule (ligand) and receptor

is highly specific. A shape change in a receptor is often theinitial transduction of the signal.


.. Receptors in the Plasma Membrane A G protein-coupledreceptor is a membrane receptor that works with the help of acytoplasmic G protein. Ligand binding activates the receptor,which then activates a specific G protein, which activates yetanother protein, thus propagating the signal along a signaltransduction pathway.

Receptor tyrosine kinases react to the binding of signaling molecules by forming dimers and then adding phosphategroups to tyrosines on the cytoplasmic part of the other subunit ofthe dimer. Relay proteins in the cell can then be activated by binding to different phosphorylated tyrosines,allowing this receptor to trigger several pathways at once.

Specific signaling molecules cause ligand-gated ion channels in a membrane to open or close, regulating the flow ofspecific ions.

.. Intracellular Receptors Intracellular receptors are cytoplasmic or nuclear proteins. Signaling molecules that are small orhydrophobic and can readily cross the plasma membrane usethese receptors.

Activity Reception

.i,'IIiI'-11.3Transduction: Cascades of molecular interactions relaysignals from receptors to target molecules in the cell(pp.214-218)

.. Signal Transduclion Pathways At each step in a pathway,the signal is transduced into a different form, commonly ashape change in a protein.

.. Protein Phosphorylation and Dephosphorylation Manysignal transduction pathways include phosphorylation cascades, in which a series of protein kinases each add a phosphate group to the next one in line, activating it. Phosphataseenzymes soon remove the phosphates.

.. Small Molecules and Ions as Second Messengers Secondmessengers, such as cyclic AMP (cAMP) and CaH , diffusereadily through the cytosol and thus help broadcast signalsquickly. Many G proteins activate adenylyl cyclase, whichmakes cAMP from ATP. Cells use Ca2+ as a second messenger in both G-protein and tyrosine kinase pathways. The tyrosine kinase pathways can also involve two other secondmessengers, DAG and IP3.IP3 can trigger a subsequent increase in CaH levels.

Activity Sign.l Tr.nsduction P.thw.ys

.i,IIIi"_ 11.4Response: Cell signaling leads to regulation oftranscription or cytoplasmic activities (pp. 218-223).. Nuclear and Cytoplasmic Responses Some pathways reg-

ulate genes by activating transcription fJctors, proteins thatturn specific genes on or off. In the cytoplasm, signaling pathways regulate, for example, enzyme activity and cytoskeletonrearrangement. which can lead to cell shape changes.

.. Fine-Tuning of the Response Each catalytic protein in a signaling pathway amplifies the signal by activating multiplecopies of the next component of the pathway; for long pathways, the total amplification may be a millionfold or more.The particular combination of proteins in a cell gives the cellgreat specificity in both the signals it detects and the re-


sponses it carries out. Scaffolding proteins can increase signaltransduction efficiency. Pathway branching and cross-talkfurther help the cell coordinate incoming signals. Signal response is terminated quickly by the reversal of ligand binding.

Activity Cellul.r Responses

Acti,ity Build a Sign.ling P.thway

.i11,,1'-11.5Apoptosis (programmed cell death) integrates multiplecell-signaling pathways (pp. 223-225).. Apoptosis is a type of programmed cell death in which cell

components are disposed of in an orderly fashion, withoutdamage to neighboring cells.

.. Apoptosis in the Soil Worm Caellorhabditis elegallsApoptosis occurs at defined times during embryonic development of C. elegans. A protein (Ced-9) in the mitochondrialmembrane acts as a brake; when released by a death signal, itallows activation of caspases that carry out apoptosis.

.. Apoptotic Pathways and the Signals That Trigger ThemSeveral apoptotic pathways exist in the cells of humans andother mammals, and these pathways may be triggered in different ways. A major pathway involves pore formation in the outermitochondrial membrane, which leads to release of factors thatactivate caspases. Signals can originate from outside or insidethe cell.

TESTING YOUR KNOWLEDGE

SELF-QUIZ

I. Phosphorylation cascades involving a series of protein kinasesare useful for cellular signal transduction becausea. they are species specific.b. they always lead to the same cellular response.c. they amplify the original signal manyfold.d. they counter the harmful effects of phosphatases.e. the number of molecules used is small and fixed.

2. Binding of a Signaling molecule to which type of receptor leadsdirectly to a change in the distribution of ions on opposite sidesof the membrane?a. receptor tyrosine kinaseb. G protein-coupled receptorc. phosphorylated receptor tyrosine kinase dimerd. ligand-gated ion channele. intracellular receptor

3. The actiV'Jtion of receptor tyrosine kinases is characterized bya. dimerization and phosphorylation.b. IP3 binding.c. a phosphorylation cascade.d. GTP hydrolysis.e. channel protein shape change.

4. Which observation suggested to Sutherland the involvement ofa second messenger in epinephrine's effect on liver cells?a. Enzymatic activity was proportional to the amount of

calcium added to a cell-free extract.b. Receptor studies indicated that epinephrine was a ligand.

c. Glycogen breakdown was observed only when

epinephrine was administered to intact cells.

d. Glycogen breakdown was observed when epinephrine and

glycogen phosphorylase were combined.

e. Epinephrine was known to have different effects on

different types of cells.

5. Protein phosphorylation is commonly involved with all of the

following excepta. regulation of transcription by extracellular signaling

molecules.

b. enzyme activation.

c. activation ofG protein-coupled receptors.

d. activation of receptor tyrosine kinases.

e. activation of protein kinase molecules.

6. Lipid-soluble signaling molecules, such as testosterone, cross

the membranes of all cells but affect only target cells because

a. only target cells retain the appropriate DNA segments.

b. intracellular receptors are present only in target cells.

c. most cells lack the Ychromosome required.

d. only target cells possess the cytosolic enzymes that

transduce the testosterone.

e. only in target cells is testosterone able to initiate the

phosphorylation cascade leading to activated

transcription factor.

7. Consider this pathway: epinephrine ---> G protein-coupled

receptor ---> G protein -. adenylyl cyclase -. cAMP. Identify the

second messenger.

a. cAMP

b. G protein

c. GTP

d. adenylyl cyclase

e. G protein-coupled receptor

8. Apoptosis involves all but the following:a. fragmentation ofthe DNA

b. cell-signaling pathwaysc. activation of cellular enzymes

d. lysis of the cell

e. digestion of cellular contents by scavenger cells

9. "P.'i.i'" Draw the following apoptotic pathway, which op

enltes in human immune cells. A death signal is received whena molecule called Fas binds its cell-surfdce receptor. The bind

ing of many Fas molecules to receptors causes receptor cluster

ing. The intracellular regions ofthe receptors, when together,bind adapter proteins. These in turn bind to inactive forms of

caspase-8, which become activated and activate caspase-3, in

turn. Once activated, caspase-3 initiates apoptosis.

For SeIf·Qlliz answers, see Appendix A.

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EVOLUTION CONNECTION

10. \Xfhat evolutionary mechanisms might account for the origin

and persistence of cell-to-cell signaling systems in unicellular

prokaryotes?

SCIENTIFIC INQUIRY

II. Epinephrine initiates a signal tmnsduction pathway that in

volves production of cyclic AMP (cAM(l) and leads to the

breakdown of glycogen to glucose, a major energy source forcells. But glycogen breakdown is actually only part of a "fight

or-flight response" that epinephrine brings about; the overall

effect on the body includes increased heart rate and alertness,

as well as a burst ofenergy. Given that caffeine blocks the activ

ity ofcAMP phosphodiesterase, propose a mechanism by

which caffeine ingestion leads to heightened alertness and

sleeplessness.

Biological Inquiry: A Workbook of In,'rstigati..., Casrs Explore cellsignaling processes in the hedgehog signaling pathway with the CaSe·Shh: Silencing the Hedgehog Pathway,·

SCIENCE, TECHNOLOGY, AND SOCIETY

12. The aging process is thought to be initiated at the cellular level.

Among the changes that can occur after a certain number of

cell divisions is the loss of a cell's ability to respond to growth

factors and other chemical signals. Much research into aging is

aimed at understanding such losses, with the ultimate goal of

significantly extending the human life span. Not everyone,

however, agrees that this is a desirable goaL Iflife expectancy

were greatly increased, what might be the social and ecological

consequences? How might we cope with them?


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Chapter 11