Chapter 11

Cell Communication

AP Biology

Overview: The Cellular Internet

Cell-to-cell communication is important for multicellular organisms The trillions of cells that make up these organisms have to be able to communicate with each other so they can coordinate their activities This communication enables organisms to not only develop from a fertilized egg, but also to survive and reproduce

Biologists have recently discovered some universal mechanisms for cell recognition, which provides additional evidence for the evolutionary relatedness of all life The same small set of cell-signaling mechanisms shows up time and again in many lines of biological research, including: Embryonic development Hormone action Cancer

Cells most often communicate with each other by chemical signals

In this chapter, we focus on the main mechanisms by which cells receive, process, and respond to chemical signals sent from other cells

Concept 11.1: External Signals Are Converted to Responses Within the Cell

Cell Signaling in Microorganisms

Communication among microorganisms is a window into the role of cell signaling in the evolution of life on Earth Researchers have learned much about cell signaling by studying mating in yeast cells They have discovered that cells of a yeast known as Saccharomyces cerevisiae identify their mates by chemical signaling

Communication Between Mating Yeast Cells

There are 2 sexes (mating types) in this species of yeast:

Type a: secrete a signaling molecule called a factor that binds to

receptor proteins on nearby cells factor that binds receptors on
factor

Type : secrete a signaling factor called nearby a cells

Receptor

Though these mating factors do not actually enter the cells,

Type, A Type

they cause the 2 types of cells to grow toward each other

This results in fusion (mating) of 2 cells of opposite types The new a/ cell contains all genes both original cells a
a factor

This combination of genetic resources provides advantages to descendants of these cells that arise by subsequent cellular division a/

Evolution of Cell Signaling

Thus, mating in yeast involves a change (transduction) in the signaling molecule

into some form that brings about the cellular response of mating
A signal transduction pathway is a series of steps by which a signal on a cells surface is converted into a specific cellular response Many signal transduction pathways have been extensively studied in both yeast and animal cells

The molecular details of signal transduction are similar, even though

these 2 groups of organisms diverged over a billion years ago

This suggests that early versions of cell signaling evolved before

the first multicellular organisms

Cell Signaling in Prokaryotes: Quorum Sensing

Scientists believe that signaling mechanisms first evolved in ancient prokaryotes and single-celled eukaryotes

Even today, cell signaling has remained important in the microbial

world

Cells of many bacterial species secrete small molecules that can

be detected by other bacterial cells The concentration of these signaling molecules allows bacteria to sense the local density of bacterial cells This phenomenon is called quorum sensing

Cell Signaling in Prokaryotes: Biofilms

Signaling along members of a bacterial population can also lead to coordination of their activities

In response to the signal, bacterial cells

are able to come together to form aggregations called biofilms These biofilms often form structures containing regions of specialized function Ex) When food is scarce, aggregations of a soil-dwelling bacterium called myxobacteria form a structure called a fruiting body that produces thick-walled spores

capable of surviving until the environment improves

Communication by Direct Contact

Cells in a multicellular organism also usually communicate by chemical messengers They may communicate by direct contact, either: 1) Through cell junctions that connect cytoplasms of adjacent cells Gap junctions in animal cells; plasmodesmata in plant cells In these cases, signaling substances dissolved in cytosol can pass freely between adjacent cells

2) Between cell-surface molecules bound to their plasma membranes This type of communication occurs in animal cells and is called cell-cell recognition This method of signaling is important in many processes, including embryonic development and the immune response

Local Signaling: Paracrine Signaling

Messenger molecules can also be secreted by cells, allowing communication between cells that are close to one another but not necessarily adjacent to one another Some of these messenger molecules travel only short distances to influence cells in the vicinity These types of chemical messengers are called local regulators

Growth factors are one class of local regulators in animals that consist of compounds that stimulate nearby target cells to grow and divide Molecules of growth factor produced by a single cell can thus be simultaneously received to responded to by numerous cells in the vicinity This type of local signaling is called paracrine signaling

Local Signaling: Synaptic Signaling

Another, more specialized type of local signaling occurs in the animal nervous system and is called synaptic signaling In this form of signaling, an electrical signal along a nerve cell triggers secretion of a chemical signal carried by neurotransmitter molecules These neurotransmitters carrying the chemical signal diffuse across a narrow space between the nerve and target cell (often another nerve cell) called the synapse

The release of the neurotransmitter molecules into the synapse then stimulates the target cell

Local signaling in plants is not well understood

Because of their cell walls, plants must use mechanisms somewhat different from those operating locally in animals

Long-Distance Signaling
Both animal and plant cells use chemicals called hormones for long-distance signaling

In animals, these hormones travel through the circulatory system to target cells
in other parts of the body The process of hormonal signaling in animals is also called endocrine signaling

In plant cells, hormones called plant growth regulators most often reach target cells by moving through cells or by diffusing through the air as a gas Sometimes, however, these plant hormones do travel in vessels within the plant

Long Distance Signaling: Nerve Impulses

The transmission of a signal through the nervous system can also be considered an example of long-distance signaling An electrical signal travels the length of a nerve cell This electrical signal is then converted back to a chemical signal when a signaling molecule is released and crosses the synapse to another nerve cell

Here, it is converted back to an electrical signal

In this way, a nerve signal can quickly travel great distances, from

one region of the body to another

Epinephrine and the Understanding of Signal Transduction Pathways

Our current understanding of how chemical messengers act via signal transduction pathways has its origins in the work of Earl W. Sutherland Sutherland and his colleagues investigated how the animal hormone epinephrine stimulates the breakdown of the storage polysaccharide glycogen in liver and skeletal muscle cells Glycogen breakdown releases the sugar glucose-1-phosphate, which the cell then converts to glucose-6-phosphate The cell can then use this compound (an early intermediate in glycolysis) for energy production Alternatively, the compound can instead be stripped of phosphate and released from the cell and into the blood as glucose, This glucose can then be absorbed and used as fuel by other cells throughout the body

Thus, one effect of epinephrine is the mobilization of fuel reserves during times of physical or mental stress

Epinephrine and the Understanding of Signal Transduction Pathways

Sutherlands research team discovered that epinephrine stimulates glycogen breakdown by somehow activating a cytosolic enzyme called glycogen phosphorylase Glycogen breakdown, however, only occurred in intact cells

When epinephrine was added to a test-tube mixture containing the enzyme

and its substrate, glycogen, no breakdown occurred

This result showed that: 1) Epinephrine does not interact directly with glycogen phosphorylase Instead, an intermediate step or series of steps must be occurring

inside the cell

2) The plasma membrane is somehow involved in transmitting the epinephrine signal

Stages of Cell Signaling: Reception

Sutherlands early work thus suggested that the process going on at the receiving end of a cellular conversation can be dissected into 3 stages: Reception Transduction Response 1) Reception: the target cell detects a signaling

molecule coming from outside cell

A chemical signal is detected when the signaling molecule binds to receptor protein located either at the cell surface or inside the cell Ex) Epinephrine binds to receptor proteins on/in liver and skeletal muscle cells

Stages of Cell Signaling: Transduction

2) Transduction: binding of the signaling molecule changes the receptor protein is some way that initiates the process of transduction The signal is then converted to a form that can bring about a specific cellular response Ex) In Sutherlands system, binding of epinephrine to a receptor protein in a liver or skeletal muscle cells plasma membrane leads to activation of glycogen phosphorylase

This sometimes occurs in a single step More often, however, it requires a sequence of changes in a series of different molecules This type of transduction is referred to as a signal transduction pathway The molecules in this type of pathway are often called relay molecules

Stages of Cell Signaling: Response

3) Response: the transduced signal triggers a specific cellular response

Ex) The breakdown of glycogen by the activated glycogen

phosphorylase

The cell-signaling process helps ensure that crucial activities occur in the
right cells at the right times and in proper coordination with other cells of the organism

Concept Check 11.1

1) Explain how signaling is involved in ensuring that yeast cells
only fuse with cells of the opposite mating type.

2) Explain how nerve cells provide examples of both local and

long-distance signaling.

3) When epinephrine is mixed with glycogen phosphorylase

and glycogen in a test tube, is glucose-1-phosphate generated?

Why or why not?

4) In liver cells, glycogen phosphorylase acts in which of the 3 stages of the signaling pathway associated with an epinephrine-initiated signal?

Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape

Specificity of Signaling Molecules

Receptor proteins on or in target cell allow only these cells to hear signals and respond to them This is because the signaling molecule is complementary in shape to a specific site on the receptor, allowing it to attach there with a lock/key fit

The signaling molecule is called a ligand

Binding of a ligand generally causes the receptor protein to change shape This shape change may directly activate the receptor, allowing it to interact with other cellular molecules Alternatively, the shape change may cause aggregation of 2 or more receptor molecules, leading to further molecular events inside the cell

Ligand Binding and Signal Receptors

In a general way, ligand binding is similar to the binding of an allosteric regulator to an enzyme

Recall: binding of an allosteric regulator causes a shape change

that either promotes or inhibits enzyme activity

In the case of signal transduction, ligand binding alters the ability of the
receptor to transmit the signal

Most signal receptors are plasma membrane proteins, though some are located inside the cell Their ligands are water-soluble and often too large to pass freely through plasma membrane

Receptors in the Plasma Membrane

Most water-soluble ligands bind to specific sites on receptor proteins embedded in the plasma membrane These receptors then transmit information from the extracellular environment to the inside of the cell 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

G proteins are special proteins that bind the energy-rich molecule GTP
The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive If GTP is bound to the G protein, the G protein is active

G protein-coupled receptor proteins are similar in structure Each have 7 alpha helices spanning their plasma membranes Specific loops between helices form binding sites for signaling molecules and G protein molecules

G Protein-Coupled Receptor Function

G protein-coupled receptor systems are widespread and diverse in function They are involved in embryonic development, as well as sensory reception (vision and smell in humans) They are also involved in many human diseases: Bacterial infections that cause cholera, pertussis (whooping cough), and botulism all cause illness by producing toxins that

interfere with G-protein function

Pharmacologists estimate that up to 60% of all medicines used today exert their effects by influencing G-protein pathways

G Protein-Coupled Receptors: Step 1

The G protein is loosely attached to cytoplasmic side of membrane It functions as a molecular switch that is either on or off Inactive form: GDP (guanosine diphosphate) is bound to G protein Active form: GTP (guanosine triphosphate) is bound to G protein The receptor and G protein work together with another protein This other protein is usually an enzyme

G Protein-Coupled Receptors: Step 2

When the appropriate signaling molecule binds to extracellular side of receptor: The receptor changes shape

The receptor is now activated

The cytoplasmic side of the receptor can then bind an inactive G protein This causes GTP to displace GDP This, in turn, activates the G protein

G Protein-Coupled Receptors: Step 3

The activated G protein dissociates from receptor and diffuses along membrane The G protein then binds to an enzyme This enzyme, in turn, changes shape and becomes activated The activated enzyme can then trigger the next step in a pathway leading to a cellular response

G Protein-Coupled Receptors: Step 4

The changes in the enzyme and G protein are only temporary The G protein also functions as a GTPase enzyme and hydrolyzes its bound GTP to GDP This causes the G protein to become inactivated and leave the enzyme The enzyme can then return to its original state

Thus, both the G protein and the enzyme are now available for reuse

The GTPase function of the G protein allows the pathway to shut down rapidly when its signaling molecule is no longer present

Receptor Tyrosine Kinases

Receptor tyrosine kinases belong to a major class of plasma membrane receptors that are 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 It catalyzes the transfer of a phosphate group from ATP to the amino acid tyrosine on a substrate protein

A receptor tyrosine kinase complex can trigger multiple signal transduction pathways at once This helps the cell regulate and coordinate many aspects of cell growth and reproduction This ability of a single ligand-binding event to trigger so many pathways is also a key difference between receptor tyrosine kinases and G proteincoupled receptors

Abnormal receptor tyrosine kinases that function even in the absence of signaling molecules may contribute to some kinds of cancer

Receptor Tyrosine Kinases: Step 1

Before the signaling molecule binds, the receptors exist as individual

polypeptides
The structure of each polypeptide includes: An extracellular ligand-binding site An alpha helix spanning the membrane An intracellular tail containing multiple tyrosines

Receptor Tyrosine Kinases: Step 2

Binding of a signal molecule (often a growth factor) causes 2 receptor polypeptides to associate closely with each other This forms a structure called a dimer This process is called dimerization

Receptor Tyrosine Kinases: Step 3

Dimerization activates the tyrosine kinase region of each polypeptide Each tyrosine adds a phosphate from ATP to a tyrosine on the tail of the other polypeptide

Receptor Tyrosine Kinases: Step 4

The now fully activated receptor protein is recognized by specific relay proteins inside the cell

These relay proteins each bind to a specific phosphorylated tyrosine

Binding results in a structural change that activates the bound relay protein

Each of these activated relay proteins can then trigger a transduction pathway
that leads to a specific cellular response

Ligand-Gated Ion Channels

A ligand-gated ion channel is a type of membrane receptor containing a region that can act as a gate when the receptor changes shape When a signaling molecule binds as a ligand to the receptor, the gate open or closes, allowing or blocking the flow of specific ions (ex: Na+ or Ca2+) through a channel in the receptor Like other membrane receptors, ligand-gated ion channels bind their ligands at a specific site on their extracellular sides

Ligand-gated ion channels are particularly important in the nervous system Neurotransmitter molecules released at a synapse between 2 nerve cells bind as ligands to ion channels on the receiving cell, causing the channels to open Ions can thus flow in (or out), which then triggers an electrical signal that propagates down the length of the receiving cell

Some gated ion channels are controlled by electrical signals rather than ligands These are known as voltage-gated ion channels and are also crucial to the functioning of the nervous system

Ligand-Gated Ion Channels

1) The gate of a ligand-gated ion channel receptor remains closed until a ligand binds to the receptor

2) The ligand binds to the receptor, causing its gate to

open Specific ions can then flow through the channel

Fig. 11-7d

1 Signaling molecule (ligand)

Gate closed

Ions

Ligand-gated ion channel receptor

Plasma membrane

This can cause a rapid change in the concentrations of these ions inside the cell

2 Gate open

This change may directly affect the activity of the

cell in some way
Cellular response

3) When the ligand dissociates from its receptor, the gate

3 Gate closed

closes and ions can no longer enter/leave the cell

Intracellular Receptors
Some receptor proteins are intracellular, found either in the cytosol or the nucleus of target cells To reach these receptors, chemical messengers must pass through the target cells plasma membrane Small or hydrophobic chemical messengers can readily cross the phospholipid interior of the membrane and activate receptors Ex) Steroid and thyroid hormones of animals, gases like NO (nitric oxide)

Intracellular Receptors: Testosterone

The behavior of testosterone is representative of steroid hormones Testosterone is secreted by cells of the testis and travels through the blood to enter cells all over the body In the cytoplasm of target cells, testosterone binds to the receptor protein and activates it

With the testosterone attached, the active form of the receptor protein then
enters the nucleus Here, the activated hormone-receptor complex acts as a transcription factor, turning on specific genes that control male sex characteristics Transcription factors are special proteins that control which genes are

transcribed into mRNA (and thus which genes are turned on) in a
particular cell at a particular time

Intracellular Receptors: Testosterone As An Example

Fig. 11-8-5 1) The steroid hormone testosterone passes through the plasma membrane

Hormone (testosterone)

EXTRACELLULAR FLUID

2) Testosterone binds to a receptor protein in the cytoplasm, activating it

Receptor protein

Plasma membrane

3) The hormone-receptor complex enters the nucleus and binds to and turns on specific genes that control male sex characteristics
DNA

Hormonereceptor complex

4) The bound receptor protein acts as a transcription factor, stimulating the transcription of the gene into mRNA 5) The mRNA is translated into a specific protein

mRNA

NUCLEUS

New protein

CYTOPLASM

Concept Check 11.2 1) Nerve growth factor (NGF) is a water-soluble

signaling molecule. Would you expect the receptor

for NGF to be intracellular or in the plasma

membrane? Why?
2) What would the effect be if a cell made defective receptor tyrosine kinase proteins that

were unable to dimerize?

Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell

Transduction: Multi-Step Pathways

The transduction stage of cell signaling is usually a multistep pathway Steps often include: Activation of proteins by addition or removal of phosphate groups Release of other small molecules or ions that act as messengers

One benefit of multiple steps is that it can amplify a signal This means that only a few molecules can produce a large cellular response

Multistep pathways also provide more opportunities for coordination and regulation of the cellular response This allows fine-tuning of the cellular response

Signal Transduction Pathways

In multistep pathways, the binding of a specific signaling molecule to a plasma membrane receptor triggers the 1st step in a chain of molecular interactions This chain of events is known as a signal transduction pathway

Similar to falling dominoes, the signal-activated receptor activates 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, also known as relay molecules, are mostly proteins

It is important to remember that the original signaling molecule is not physically passed along the signal transduction pathway In most cases, this signaling molecule never even enters the cell Rather, the signal is relayed along the pathway as certain information is passed on

At each step, the signal is transduced into a different form, usually a shape change in a protein
This shape change is often brought about by phosphorylation

Protein Phosphorylation
Recall: the general name for an enzyme that transfers phosphate groups from ATP to a protein is a protein kinase Most cytoplasmic protein kinases act on proteins different from themselves (unlike receptor tyrosine kinases) Another distinction is that most cytoplasmic protein kinases phosphorylate either the amino acid serine or threonine (rather than tyrosine)

Many of the relay molecules in signal transduction pathways are protein kinases
In turn, these protein kinase relay molecules often act on other protein kinases in the pathway

Phosphorylation of the proteins along a signal transduction pathway causes these molecules to change shape Each shape change results from the interaction of newly added phosphate groups with charged and polar amino acids The addition of a phosphate group also usually changes the protein from an inactive to an active form

Importance of Protein Kinases

Protein kinases are very important in maintaining normal body function About 2% of human genes are thought to code for various protein kinases A single cell, in fact, may have 100s of different kinds of protein kinases, each specific for a different substrate protein Together, these protein kinases likely regulate most of the 1000s of

proteins in a cell
These proteins, in turn, regulate functions such as cell reproduction

Thus, abnormal activity of such kinases can cause abnormal cell

growth and contribute to the development of cancer

Protein Dephosphorylation
Dephosphorylation is equally important in the phosphorylation cascade of a signal transduction pathway Protein phosphatases are enzymes that can rapidly remove phosphate groups from proteins

Dephosphorylation inactivates protein kinases Thus, if the initial signal is no longer present, protein phosphatases provide a way to turn off signal transduction pathways

Protein phosphatases also recycle protein kinases that have been phosphorylated This allows the cell to continually respond to new extracellular signals

The activity of a protein regulated by phosphorylation thus depends on a balance between active kinase molecules and active phosphatase molecules The system of phosphorylation and dephosphorylation acts a molecular switch in the cell, turning activities on or off as required

A Phosphorylation Cascade
1) 2) 3) 4) A relay molecule activates protein kinase 1 The active protein kinase 1 transfers a phosphate group from ATP to an inactive protein kinase 2, thus activating this 2nd kinase The now-active protein kinase 2 catalyzes the phosphorylation and activation of protein kinase 3 Fig. 11-9
Signaling molecule

Active protein kinase 3 phosphorylates a protein (pink) that elicits a cellular response Enzymes called protein phosphatases (PP) catalyze removal of phosphate groups, making them inactive and available for reuse

Receptor Activated relay molecule

Inactive protein kinase 1

Active protein kinase 1

Inactive protein kinase 2
Pi ATP ADP

Ph os ph yla or

5)

PP

Active protein kinase 2

ATP ADP

n tio ca sc ad e

Inactive protein kinase 3

Pi

PP
Inactive protein

Active protein kinase 3

ATP ADP

Pi

PP

Active protein

Cellular response

Small Molecules and Ions as Second Messengers

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 pathways first messenger Second messengers can spread through the cell by simple diffusion because of their chemical nature

Second messengers participate in pathways initiated by both G protein-coupled

receptors and receptor tyrosine kinases Cyclic AMP and calcium ions are two commonly used second messengers A large variety of relay proteins are sensitive to the cytosolic concentration of one or the other of these second messengers

Cyclic AMP
Cyclic adenosine monophoasphate (cyclic AMP or cAMP) is one of the most widely used second messengers in signal transduction pathways
Fig. 11-10

An enzyme embedded in the plasma membrane called adenylyl cyclase converts ATP to cAMP in response to an extracellular signal Ex) Epinephrine is just one of many hormones and other signaling molecules that trigger formation of cAMP

Adenylyl cyclase

Phosphodiesterase

Pyrophosphate P ATP Pi cAMP AMP

Cyclic AMP and Epinephrine

In the case of epinephrine, adenylyl cyclase is not stimulated by epinephrine directly Instead, epinephrine outside the cell binds to a specific receptor protein which, in turn, activates adenylyl cyclase, thus catalyzing the synthesis of many cAMP molecules In this way, the normal cellular concentration of cAMP can be boosted 20fold in just a matter of seconds

cAMP does not persist for long in the absence of an extracellular signal, however
Fig. 11-10

Another enzyme called phosphodiesterase converts cAMP to AMP Another surge of epinephrine would be necessary to boost cytosolic concentrations of cAMP again

Adenylyl cyclase

Phosphodiesterase

Pyrophosphate P ATP Pi cAMP AMP

Receptors Involved in the Regulation of cAMP

Research has brought to light other components of cAMP pathways These include G proteins, G Fig. 11-11 protein-coupled receptors, and protein kinases

First messenger

The immediate effect of cAMP is usually the activation of a serine/threonine kinase called protein kinase A This activated kinase then phosphorylates various other proteins

G protein

Adenylyl cyclase

G protein-coupled receptor

GTP ATP cAMP

Second messenger Protein kinase A

Cell metabolism is also regulated by other G-protein systems that inhibit adenylyl cyclase

Cellular responses

In this case, a different molecule activates a different receptor, activating an inhibitory G protein

cAMP and Cholera

Cholera is a disease that is frequently epidemic in places where the water supply is contaminated with human feces People acquire the cholera bacterium (Vibrio cholerae) by drinking this contaminated water These bacteria then colonize the lining of the small intestine and produce a toxin

The cholera toxin is an enzyme that chemically modifies a G protein involved in regulating salt and water secretion This modified G protein is unable to hydrolyze GTP to GDP, leaving the protein stuck in its active form

This means that adenylyl cyclase is continuously stimulated to make cAMP

The resulting high concentration of cAMP causes intestinal cells to secrete large amounts of salts, also causing water to quickly follow by osmosis Thus, an infected person quickly develops profuse diarrhea, and if left untreated, can soon die from the loss of water and salts

Useful Application of cAMP

Our understanding of signaling pathways involving cAMP and related messengers has also allowed us to develop treatments for certain human conditions

Cyclic GMP (cGMP) is a related signaling molecule whose effects include

relaxation of smooth muscle cells in artery walls

A compound that inhibits hydrolysis of cGMP to GMP thus prolongs the signal This compound was originally prescribed for chest pains because it increased blood flow to the heart Under the trade name Viagra, however, this compound is now widely used as a treatment for erectile dysfunction It allows increased blood flow to the penis, which optimizes physiological conditions for penile erections

Calcium Ions as Second Messengers

Calcium ions (Ca2+) are even more widely used than cAMP as second messengers in signal transduction pathways Increasing the cytosolic calcium concentration causes many responses in animal cells, including: Muscle cell contraction Secretion of certain substances Cell division

Increases in cytosolic calcium concentrations can also trigger various signaling pathways in plants, including the pathway for greening in response to light

Cells use calcium ions as a second messenger in both G-protein and receptor
tyrosine kinase pathways

Calcium Ions Regulation

The cytosolic Ca2+ concentration is normally much lower than concentrations in the extracellular environment and in the ER

The level of calcium in the blood and extracellular fluid of an animal

Fig. 11-12

often exceeds that in the cytosol by more than 10,000X Cells maintain this concentration gradient by actively transporting Ca2+ ions out of the cell by protein pumps At the same time, they are also actively

EXTRACELLULAR FLUID Ca2+ pump ATP Mitochondrion

Plasma membrane

Nucleus

CYTOSOL

Ca2+ pump Endoplasmic reticulum (ER) ATP Ca2+ pump

imported out of the cell and into the ER

Key High [Ca2+] Low [Ca2+]

Calcium Ions and Inositol Triphosphate (IP3)

Certain signals relayed by a signal transduction pathway may trigger an increase in cytosolic calcium levels

Rises in cytosolic calcium concentrations usually occur by

mechanisms that release calcium ions from the ER Pathways leading to calcium release involve still other second messengers, including: Inositol triphosphate (IP3) Diacylglycerol (DAG) These 2 messengers are produced by cleavage of a certain type of phospholipid in the plasma membrane called PIP2

Calcium Ions and IP3 in Signaling Pathways

1) 2) A signaling molecule binds to a receptor, leading to activation of phospholipase C Phospholipase C cleaves a plasma membrane phospholipid (PIP2) into DAG and IP3 3) DAG also functions as a 2nd messenger in other pathways
Fig. 11-13-3

IP3 diffuses through the cytosol and binds to IP3-gated

calcium channels in the ER,

causing them to open 4) Ca2+ ions flow out of the ER (down their concentration gradients), raising cytosolic Ca2+ concentration 5) The released Ca2+ ions activate the next protein in one or more signaling pathways

EXTRACELLULAR FLUID

Signaling molecule (first messenger)

G protein

2
DAG

GTP

G protein-coupled receptor

Phospholipase C

PIP2 IP3 (second messenger)

IP3-gated calcium channel

3
Various proteins activated

Endoplasmic reticulum (ER)

Ca2+ Ca2+ (second messenger )

Cellular responses

CYTOSOL

Concept Check 11.3

1) What is a protein kinase, and what is its role in signal transduction pathways?

2) When a signal transduction pathway involves a phosphorylation cascade,

how does the cells response get turned off?

3) What is the actual signal that is being transduced in any signal

transduction pathway. In other words, in what way is information passed from the exterior to the interior of the cell?

4) Upon activation of phospholipase C by ligand binding to a receptor, what effect does the IP3-gated calcium channel have on calcium ion concentration

in the cytosol?

Concept 11.4: Response: Cell Signaling Leads to Regulation of Transcription or Cytoplasmic Activities

Nuclear Responses
Signal transduction pathways ultimately lead to regulation of one or more cellular activities This response may occur in nucleus or cytoplasm

Many pathways regulate protein synthesis by turning genes on or off in the nucleus
Fig. 11-14

Growth factor Receptor

Reception

The final activated molecule may function as a transcription factor This activated transcription factor may
Phosphorylatio n cascade Transduction

turn a gene on so it can be

transcribed and translated into a specific protein In other cases, a transcription factor may turn a gene off, so that a protein stops being manufactured

CYTOPLASM

Inactive transcription factor

Active transcription factor

P

Response

DNA Gene NUCLEUS mRNA

Cytoplasmic Responses
Other pathways regulate the activity of proteins rather than their synthesis Ex) A signal may cause a change in cell metabolism
Fig. 11-15 Reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)

The response of liver cells to signaling by the hormone epinephrine helps regulate cell energy metabolism by affecting enzyme activity As each molecule is activated, the response is amplified 1 receptor protein can activate ~100 G proteins Each activated enzyme can then act on many of its substrates during the next reaction in the cascade

Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase

Binding of epinephrine eventually activates an enzyme that catalyzes breakdown of glycogen into glucose-1-phosphate molecules

Active glycogen phosphorylase (106) Response Glycogen Glucose-1-phosphate (108 molecules)

the

Directional Growth in Yeast

Signaling pathways can also lead to responses that affect the physical characteristics of a cell, such as cell shape Ex) The mating of yeast depends on the growth of projections in one cell toward another cell of opposite mating type
Fig. 11-16a

Binding of the mating factor causes this directional growth When the mating factor binds, it activates signaling-pathway kinases that affect the orientation and growth of cytoskeletal filaments The cell projections emerge from regions of the plasma RESULTS membrane exposed to the highest concentration of the mating factor As a result, projections are oriented toward cell of opposite mating type (the source of the signaling molecule)

Fine-Tuning of the Response

Regardless of whether the response occurs in the nucleus or cytoplasm, multistep pathways allow fine-tuning of responses at multiple points

These multistep pathways provide 2 important benefits:

The signals can be amplified, thus amplifying the response

They provide different points at which the cells response can be

regulated This allows coordination of different signaling pathways It also contributes to the specificity of the response The overall efficiency of the response is also enhanced by scaffolding proteins Termination of the signal is also a crucial point in fine-tuning a response

Signal Amplification
Enzyme cascades amplify the cells response to a signal At each step in the cascade, the number of activated products is much greater than in preceding step This amplification effect occurs because activated proteins persist long enough to process many substrate molecules before becoming inactive

Ex) Only a small number of epinephrine molecules binding to

receptors on the surfaces of liver and muscle cells can lead

to the release of millions of glucose molecules from glycogen

The Specificity of Cell Signaling and Coordination of the Response

Different cells respond only to specific signals, even though they are constantly exposed to many different signaling

molecules
In addition, even though some signals trigger responses in more than one type of cell, these responses can be different

Ex) Epinephrine stimulates liver cells to break down

glycogen; in heart cells, this hormone causes

contraction, leading to a more rapid heartbeat

The Specificity of Cell Signaling

The explanation for this specificity is that different kinds of cells have different collections of proteins This is due to the fact that different cells turn on different sets of genes

The response of a particular cell to a signal depends on its collection of signal receptor proteins, relay proteins, and proteins necessary to carry out the response Two different cells thus respond differently to the same signal because they differ in the proteins that handle and respond to the signal Ex) A liver cell responds appropriately to epinephrine by having the necessary proteins that are part of the signal transduction pathway leading to glycogen breakdown

Signaling Efficiency: Scaffolding Proteins

The efficiency of signal transduction may be increased by the presence of scaffolding proteins
Signaling molecule Plasma membrane
Fig. 11-18

These are large relay proteins to

which other relay proteins are simultaneously attached

Receptor Three different protein kinases Scaffolding protein

Scaffolding proteins can increase the

signal transduction efficiency by grouping together different proteins

involved in the same pathway

In this way, proteins are not slowed by diffusion through the viscous cytosol Ex) One scaffolding protein isolated from mouse brain cells holds 3 protein kinases and carries these kinases with it when it binds to an appropriately activated membrane receptor

Termination of the Signal

Inactivation mechanisms are also an essential aspect of cell signaling For cells to remain alert and capable of responding to incoming signals, each molecular change in their signaling pathways must last only a short time

Thus, these changes that the binding of signaling molecules to their receptors produce must be reversible When signal molecules leave the receptor, the receptor reverts to its inactive state Then, by a variety of means, the relay molecules in that pathway also return to their inactive forms GTAPase activity hydrolyzes bound GTP The enzyme phosphodiesterase converts cAMP to AMP Protein phosphatases inactivate phosphorylated kinases and other proteins

Eventually, the signal transduction pathway is terminated once the cellular response is complete

Concept Check 11.4 1) How can a target cells response to a hormone be amplified more than a million-fold?

2) If 2 cells have different scaffolding proteins,

explain how they could behave differently in response to the same signaling molecule.

Concept 11.5: Apoptosis (programmed cell death) integrates multiple cell-signaling pathways

Apoptosis
One of the most elaborate networks of signaling pathways in the cell is apoptosis Apoptosis is programmed or controlled cell suicide It occurs in damaged or infected cells or when cells have reached the end of their functional life span During this process, cellular agents chop up DNA and fragment the organelles and other cytoplasmic components The cell also shrinks and cell parts are packaged into vesicles that are engulfed and digested by scavenger cells Apoptosis protects neighboring cells from damage
Fig. 11-19

It prevents potentially destructive

enzymes from leaking out of a dying cell

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 the

nematode Caenorhabditis elegans

In these soil worms, as well as in other species, apoptosis is triggered by signals that activate a cascade of suicide proteins in cells that are destined to die There are 2 key apoptosis genes in C. elegans: ced-3 and ced-4 (ced

stands for cell death)

Proteins coded for by these genes (Ced-3 and Ced-4, respectively) are always present, but in their inactive forms Regulation therefore occurs by way of regulating protein activity rather than protein synthesis

Apoptosis in C. Elegans
In C. elegans, a protein in the outer mitochondrial membrane called Ced-9 serves as the master regulator of apoptosis
This protein acts as a brake in the absence of a signal promoting apoptosis Ced-9 stops apoptosis by inhibiting Ced-4 activity When a death signal is received by the cell, it overrides these brakes Ced-9 is then inactivated, preventing its inhibition of Ced-3 & Ced-4 Active Ced-3 then triggers a cascade of reactions leading to activation of proteases and nucleases that cut up proteins and DNA in the cell The main proteases of apoptosis are called caspases
(b) Death signal

Fig. 11-20

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

Mitochondrion

Receptor for deathsignaling molecule

Ced-4 Ced-3 Inactive proteins

(a) No death signal

Ced-9 (inactive)

Cell forms blebs

Deathsignaling molecule

Active Active Ced-4 Ced-3

Other proteases Nucleases

Activation cascade

Apoptotic Pathways in Mammals

In humans and other mammals, several different pathways that involve ~15 different caspases can carry out apoptosis

The pathway that is used depends on the type of cell and on the particular
signal that triggers apoptosis

One major pathway involves mitochondrial proteins Apoptotic proteins can form molecular pores in the outer mitochondrial membrane This causes the membrane to leak and release proteins that promote apoptosis The process of mitochondrial apoptosis in mammals uses proteins similar to the nematode proteins Ced-3, Ced-4, and Ced-9

Apoptotic Pathways and the Signals That Trigger Them

Apoptosis can be triggered in by a variety of mechanisms, including: An extracellular death-signaling ligand released by a neighboring cell When a death-signaling ligand occupies a cell-surface receptor, this binding leads to activation of caspases and other enzymes that

carry out apoptosis

Alarm signals can also originate inside the cell under certain circumstances: One of these alarm signals comes from the nucleus when its DNA has suffered irreparable damage

A second alarm signal comes from the ER when excessive protein

misfolding occurs

Role of Apoptosis in Animal Function & Development

A built-in suicide mechanism is essential to development and maintenance in all animals Similarities in apoptosis genes and mechanisms among different organisms indicates that apoptosis evolved early in animal evolution

Apoptosis is essential for the normal development of vertebrate nervous and immune systems, as well as morphogenesis of human hands and feet (paws in other mammals)
Apoptosis eliminates the cells in the interdigital regions, thus forming the digits A lower level of apoptosis in developing limbs accounts for webbed feet in water birds In the case of humans, failure of appropriate apoptosis can result in webbed fingers and toes

Apoptosis may be involved in certain degenerative diseases of the nervous system (Parkinsons and Alzheimers) Interference with apoptosis may contribute to some cancers

Concept Check 11.5 1) Give an example of apoptosis during embryonic development, and explain its function in the

developing embryo.
2) What type of protein defects could result in apoptosis occurring when it should not? What type could result in apoptosis not occurring when it should?

You should now be able to:

1. 2. 3. 4. Describe the nature of a ligand-receptor interaction and state how such interactions initiate a signal-transduction system Compare and contrast G protein-coupled receptors, tyrosine kinase receptors, and ligand-gated ion channels List two advantages of a multistep pathway in the transduction stage of cell signaling Explain how an original signal molecule can produce a cellular response when it may not even enter the target cell

5.
6. 7.

Define the term second messenger; briefly describe the role of these molecules in signaling pathways
Explain why different types of cells may respond differently to the same signal molecule Describe the role of apoptosis in normal development and degenerative disease in vertebrates