Chapter 11~Chapter 11~ Cell Cell CommunicationCommunication

Signal-transduction Signal-transduction pathwaypathway

DefDef: Signal on a cell’s surface is converted into a : Signal on a cell’s surface is converted into a specific cellular responsespecific cellular response

Local signaling Local signaling (short distance): (short distance): √ Paracrine (growth factors)√ Paracrine (growth factors)

√ Synaptic (neurotransmitters)√ Synaptic (neurotransmitters) Long distanceLong distance: hormones: hormones

Stages of cell signalingStages of cell signaling

Sutherland (‘71)Sutherland (‘71) Glycogen depolymerization by epinephrineGlycogen depolymerization by epinephrine 3 steps:3 steps:

•Reception: target cell detection •Reception: target cell detection •Transduction: single-step or series of changes•Transduction: single-step or series of changes

•Response: triggering of a specific cellular •Response: triggering of a specific cellular responseresponse

Signal molecules and Signal molecules and Receptor Proteins Receptor Proteins

A cell targeted by a particular chemical A cell targeted by a particular chemical signal has a receptor protein that recognizes signal has a receptor protein that recognizes the signal molecule.the signal molecule.• Recognition occurs when the signal binds to a Recognition occurs when the signal binds to a

specific site on the receptor because it is specific site on the receptor because it is complementary in shape.complementary in shape.

When When ligandsligands (small molecules that bind (small molecules that bind specifically to a larger molecule) attach to specifically to a larger molecule) attach to the receptor protein, the receptor typically the receptor protein, the receptor typically undergoes a change in shape.undergoes a change in shape.• This may activate the receptor so that it can This may activate the receptor so that it can

interact with other molecules.interact with other molecules.• For other receptors this leads to the collection of For other receptors this leads to the collection of

receptors.receptors.

G-Protein-Linked ReceptorG-Protein-Linked Receptor A A G-protein-linked receptorG-protein-linked receptor consists consists

of a receptor protein associated with a of a receptor protein associated with a G-protein on the cytoplasmic side.G-protein on the cytoplasmic side.• The receptor consists of seven alpha The receptor consists of seven alpha

helices spanning the membrane.helices spanning the membrane.• Effective signal Effective signal

molecules include molecules include yeast mating yeast mating factors, factors, epinephrine, epinephrine, other hormones, other hormones, and and neurotransmitters.neurotransmitters.

The The G proteinG protein acts as an on-off acts as an on-off switch.switch.• If GDP is bound, the G protein is If GDP is bound, the G protein is

inactive.inactive.• If GTP is bound, the G protein is active.If GTP is bound, the G protein is active.

The G-protein system cycles between on The G-protein system cycles between on and off.and off.• When a G-protein-linked receptor is When a G-protein-linked receptor is

activated by binding with an extracellular activated by binding with an extracellular signal molecule, the receptor binds to an signal molecule, the receptor binds to an inactive G protein in membrane.inactive G protein in membrane.

• This leads the G protein to substitute GTP for This leads the G protein to substitute GTP for GDP.GDP.

• The G protein then binds with another The G protein then binds with another membrane protein, often an enzyme, membrane protein, often an enzyme, altering its activity and leading altering its activity and leading to a cellular to a cellular response. response.

Tyrosine-kinase ReceptorsTyrosine-kinase Receptors Tyrosine-kinase receptorTyrosine-kinase receptor is is

effective when the cell needs to effective when the cell needs to regulate and coordinate a variety regulate and coordinate a variety of activities and trigger several of activities and trigger several signal pathways at once.signal pathways at once.

A tyrosine-kinase is an enzyme A tyrosine-kinase is an enzyme that transfers phosphate groups that transfers phosphate groups from ATP to the amino acid from ATP to the amino acid tyrosine on a tyrosine on a protein. protein.

Individual tyrosine-kinase Individual tyrosine-kinase receptors consists of several receptors consists of several parts:parts:• an extracellular signal-binding an extracellular signal-binding

sites,sites,• a single alpha helix spanning the a single alpha helix spanning the

membrane, andmembrane, and• an intracellular an intracellular

tail with several tail with several tyrosines.tyrosines.

When ligands bind to two receptors When ligands bind to two receptors polypeptides, the polypeptides polypeptides, the polypeptides bind, forming a dimer.bind, forming a dimer.

This activates the tyrosine-kinase This activates the tyrosine-kinase section of both.section of both.

These add These add phosphates to the phosphates to the tyrosine tails of tyrosine tails of the other the other polypeptide.polypeptide.

The fully-activated receptor proteins The fully-activated receptor proteins initiate a variety of specific relay initiate a variety of specific relay proteins that bind to specific proteins that bind to specific phosphorylated tyrosine molecules.phosphorylated tyrosine molecules.• One tyrosine-kinase receptor dimer may One tyrosine-kinase receptor dimer may

activate ten or more different intracellular activate ten or more different intracellular proteins simultaneously.proteins simultaneously.

These activated relay These activated relay proteins trigger many proteins trigger many different transduction different transduction pathways and pathways and responses.responses.

Ligand-gated Ligand-gated Ion ChannelsIon Channels

Ligand-gated ion channelsLigand-gated ion channels are protein pores that open or are protein pores that open or close in response to a close in response to a chemical signal.chemical signal.• This allows or blocks ion flow, This allows or blocks ion flow,

such as Na+ or Ca2+.such as Na+ or Ca2+.• Binding by a ligand to the Binding by a ligand to the

extracellular side changes the extracellular side changes the protein’s shape and opens the protein’s shape and opens the channel.channel.

• Ion flow changes the Ion flow changes the concentration inside the cell.concentration inside the cell.

• When the ligand dissociates, the When the ligand dissociates, the channel closes.channel closes.

• Very important in the Very important in the nervous systemnervous system

The Others…The Others… Other signal receptors are dissolved in Other signal receptors are dissolved in

the cytosol or nucleus of target cells.the cytosol or nucleus of target cells. The signals pass through the plasma The signals pass through the plasma

membrane.membrane. These chemical messengers include the These chemical messengers include the

hydrophobic steroid and thyroid hydrophobic steroid and thyroid hormones of animals.hormones of animals.

Also in this group is nitric oxide (NO), a Also in this group is nitric oxide (NO), a gas whose small size allows it to slide gas whose small size allows it to slide between membrane phospholipids.between membrane phospholipids.

TestosteroneTestosterone Testosterone, like other Testosterone, like other

hormones, travels through hormones, travels through the blood and enters cells the blood and enters cells throughout the body.throughout the body.

In the cytosol, they bind and In the cytosol, they bind and activate receptor proteins.activate receptor proteins.

These activated proteins These activated proteins enter the nucleus and turn enter the nucleus and turn on genes that control male on genes that control male sex characteristics.sex characteristics.

Turning Genes OnTurning Genes On These activated proteins act as These activated proteins act as

transcription factorstranscription factors..• Transcription factors control which Transcription factors control which

genes are turned on - that is, which genes are turned on - that is, which genes are transcribed into genes are transcribed into messenger RNA (mRNA).messenger RNA (mRNA).– The mRNA molecules leave the nucleus The mRNA molecules leave the nucleus

and carry information that directs the and carry information that directs the synthesis (translation) of specific synthesis (translation) of specific proteins at the ribosome.proteins at the ribosome.

TransductionTransduction The transduction stage of signaling is The transduction stage of signaling is

usually a multistep pathway.usually a multistep pathway. These pathways often greatly amplify These pathways often greatly amplify

the signal.the signal.• If some molecules in a pathway transmit a If some molecules in a pathway transmit a

signal to multiple molecules of the next signal to multiple molecules of the next component, the result can be large numbers component, the result can be large numbers of activated molecules at the end of the of activated molecules at the end of the pathway.pathway.

A small number of signal molecules can A small number of signal molecules can produce a large cellular response.produce a large cellular response.

Also, multistep pathways provide more Also, multistep pathways provide more opportunities for coordination and opportunities for coordination and regulation than do simpler systems.regulation than do simpler systems.

Signal Transduction Signal Transduction PathwaysPathways

Signal transduction pathways act like Signal transduction pathways act like falling dominoes.falling dominoes.• The signal-activated receptor activates The signal-activated receptor activates

another protein, which activates another another protein, which activates another and so on, until the protein that produces and so on, until the protein that produces the final cellular response is activated.the final cellular response is activated.

The original signal molecule is not The original signal molecule is not passed along the pathway, it may not passed along the pathway, it may not even enter the cell.even enter the cell.• Its information is passed on.Its information is passed on.• At each step the signal is transduced into a At each step the signal is transduced into a

different form, often by a different form, often by a conformational change in a protein.conformational change in a protein.

Phosphorylation (adding Phosphorylation (adding on Phosphates)on Phosphates)

The phosphorylation of proteins by a specific The phosphorylation of proteins by a specific enzyme (a enzyme (a protein kinase)protein kinase) is a mechanism for is a mechanism for regulating protein activity.regulating protein activity.• Most protein kinases act on other substrate proteins, Most protein kinases act on other substrate proteins,

unlike the tyrosine kinases that act on themselves.unlike the tyrosine kinases that act on themselves. Most phosphorylation occurs at either serine or Most phosphorylation occurs at either serine or

threonine amino acids in the substrate protein. threonine amino acids in the substrate protein. Many of the relay molecules in a signal-Many of the relay molecules in a signal-

transduction pathway are protein kinases that transduction pathway are protein kinases that lead to a “phosphorylation cascade”.lead to a “phosphorylation cascade”.

Each protein phosphorylation leads to a shape Each protein phosphorylation leads to a shape change because of the interaction between change because of the interaction between the phosphate group and charged or polar the phosphate group and charged or polar amino acids.amino acids.

Protein phosphorylationProtein phosphorylation Protein activity Protein activity

regulationregulation Adding phosphate from Adding phosphate from

ATP to a protein ATP to a protein (activates proteins)(activates proteins)

Enzyme: protein Enzyme: protein kinases (1% of all our kinases (1% of all our genes) genes)

Example: cell Example: cell reproductionreproduction

Reversal enzyme: Reversal enzyme: protein phosphatasesprotein phosphatases

Second messengersSecond messengers

Non-protein signaling Non-protein signaling pathway (pathway (

Example: cyclic AMP Example: cyclic AMP (cAMP)(cAMP)

Ex: Glycogen Ex: Glycogen breakdown with breakdown with epinephrineepinephrine

Enzyme: adenylyl Enzyme: adenylyl cyclasecyclase

G-protein-linked receptor G-protein-linked receptor in membrane (guanosine in membrane (guanosine di- or tri- phosphate)di- or tri- phosphate)

Pathway involving cAMP as a secondary messenger.

Pathway using Ca2+ as a secondary messenger.

ScaffoldingScaffolding Rather than relying on diffusion of large Rather than relying on diffusion of large

relay molecules like proteins, many relay molecules like proteins, many signal pathways are linked together signal pathways are linked together physically by physically by scaffolding proteinsscaffolding proteins..• Scaffolding proteins may themselves be Scaffolding proteins may themselves be

relay proteins to which several other relay relay proteins to which several other relay proteins attach.proteins attach.

• This hardwiring This hardwiring enhances the enhances the speed and speed and accuracy of accuracy of signal transfer signal transfer

between cells. between cells.

Cellular responses to Cellular responses to signalssignals

Cytoplasmic Cytoplasmic activity regulationactivity regulation

Cell metabolism Cell metabolism regulationregulation

Nuclear Nuclear transcription transcription regulationregulation