Chapter 11Chapter 11

Cell Communication

I. Evolution of Cell Signaling

• Signal transduction pathway = steps by which a signal on a cell’s surface is converted into a cellular response

• Pathway similarities suggest signaling molecules evolved in prokaryotes and were modified later in eukaryotes

II. Local and Long-Distance Signaling

• Cells in a multicellular organism communicate by chemical messengers

• Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells

• Local signaling = animal cells may communicate by direct contact (cell-cell recognition)

Fig. 11-4Plasma membranes

Gap junctionsbetween animal cells

(a) Cell junctions

Plasmodesmatabetween plant cells

(b) Cell-cell recognition

• Animal cells also communicate using local regulators, messenger molecules that travel only short distances

• Long-distance signaling = plants and animals use hormones

Fig. 11-5ab

Local signaling

Target cell

Secretoryvesicle

Secretingcell

Local regulatordiffuses throughextracellular fluid

(a) Paracrine signaling (b) Synaptic signaling

Target cellis stimulated

Neurotransmitter diffuses across synapse

Electrical signalalong nerve celltriggers release ofneurotransmitter

Fig. 11-5c

Long-distance signaling

Endocrine cell Bloodvessel

Hormone travelsin bloodstreamto target cells

Targetcell

(c) Hormonal signaling

• Cell Communication Intro (Andersen 10 min)

III. Three Stages of Cell Signaling

• Sutherland discovered how epinephrine acts on cells

• Sutherland suggested that cells receiving signals went through three processes:

– Reception

– Transduction

– Response

Fig. 11-6-1

Reception1

EXTRACELLULARFLUID

Signalingmolecule

Plasma membrane

CYTOPLASM

1

Receptor

Fig. 11-6-2

1

EXTRACELLULARFLUID

Signalingmolecule

Plasma membrane

CYTOPLASM

Transduction2

Relay molecules in a signal transduction pathway

Reception1

Receptor

Fig. 11-6-3

EXTRACELLULARFLUID

Plasma membrane

CYTOPLASM

Receptor

Signalingmolecule

Relay molecules in a signal transduction pathway

Activationof cellularresponse

Transduction Response2 3Reception1

IV. Reception

• Binding between a signal molecule (ligand) and receptor is highly specific

• Shape change in a receptor is often the initial transduction (sending) of the signal

• Most signal receptors are plasma membrane proteins

V. Receptors in Membrane

• Water-soluble signal molecules bind to receptor proteins in the plasma membrane

• G protein-coupled receptor is a plasma membrane receptor that works with the help of a G protein

– G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

Fig. 11-7a

Signaling-molecule binding site

Segment thatinteracts withG proteins

G protein-coupled receptor

Fig. 11-7b

G protein-coupledreceptor

Plasmamembrane

EnzymeG protein(inactive)

GDP

CYTOPLASM

Activatedenzyme

GTP

Cellular response

GDP

P i

Activatedreceptor

GDP GTP

Signaling moleculeInactiveenzyme

1 2

3 4

• Receptor tyrosine kinases are receptors that attach phosphates to tyrosines

– A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

Fig. 11-7c

Signalingmolecule (ligand)

Ligand-binding site

Helix

TyrosinesTyr

Tyr

Tyr

Tyr

Tyr

Tyr

Receptor tyrosinekinase proteins

CYTOPLASM

Signalingmolecule

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Dimer

Activated relayproteins

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

P

P

P

P

P

P

Cellularresponse 1

Cellularresponse 2

Inactiverelay proteins

Activated tyrosinekinase regions

Fully activated receptortyrosine kinase

6 6 ADPATP

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

P

P

P

P

P

P

1 2

3 4

• Ligand-gated ion channel receptor acts as a gate when the receptor changes shape

– Signal molecule binds as a ligand to the receptor, the gate allows ions, such as Na+ or Ca2+, through a channel in the receptor

Fig. 11-7d

Signalingmolecule(ligand)

Gateclosed Ions

Ligand-gatedion channel receptor

Plasmamembrane

Gate open

Cellularresponse

Gate closed3

2

1

VI. Intracellular Receptors

• Found in cytosol or nucleus of target cells

• Small / hydrophobic chemical messengers can cross membrane and activate receptors

– steroid and thyroid hormones of animals

• Activated hormone-receptor complex can act as a transcription factor, turning on specific genes

Fig. 11-8-1

Hormone(testosterone)

Receptorprotein

Plasmamembrane

EXTRACELLULARFLUID

DNA

NUCLEUS

CYTOPLASM

Fig. 11-8-2

Receptorprotein

Hormone(testosterone)

EXTRACELLULARFLUID

Plasmamembrane

Hormone-receptorcomplex

DNA

NUCLEUS

CYTOPLASM

Fig. 11-8-3

Hormone(testosterone)

EXTRACELLULARFLUID

Receptorprotein

Plasmamembrane

Hormone-receptorcomplex

DNA

NUCLEUS

CYTOPLASM

Fig. 11-8-4

Hormone(testosterone)

EXTRACELLULARFLUID

PlasmamembraneReceptor

protein

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS

CYTOPLASM

Fig. 11-8-5

Hormone(testosterone)

EXTRACELLULARFLUID

Receptorprotein

Plasmamembrane

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS New protein

CYTOPLASM

VII. Signal Transduction Pathways

• Mostly proteins relay a signal from receptor to response

• Receptor activates another protein, which activates another, and so on, until the protein producing the response is activated

• At each step, the signal is transduced into a different form, usually a shape change in a protein

VIII. Protein Phosphorylation&Dephosphorylation

• In many pathways, signal is transmitted by a cascade of protein phosphorylations

– Protein kinases transfer phosphates from ATP to protein

– Protein phosphatases remove the phosphates from proteins (dephosphorylation)

• The phos and dephos system acts as a switch, turning activities on and off

Fig. 11-9

Signaling molecule

ReceptorActivated relaymolecule

Inactiveprotein kinase

1 Activeproteinkinase

1

Inactiveprotein kinase

2

ATPADP Active

proteinkinase

2

P

PPP

Inactiveprotein kinase

3

ATPADP Active

proteinkinase

3

P

PPP

i

ATPADP P

ActiveproteinPP

P i

Inactiveprotein

Cellularresponse

Phosphorylation cascadei

IX. Second Messengers

• The extracellular signal molecule that binds to the receptor is a pathway’s “first messenger”

• Second messengers = small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion

• Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases

• Cyclic AMP and calcium ions are common second messengers

A. Cyclic AMP

• Cyclic AMP (cAMP) = one of most widely used

• Adenylyl cyclase = enzyme in plasma memb, converts ATP to cAMP in response to an extracellular signal

Adenylyl cyclase

Fig. 11-10

Pyrophosphate

P P i

ATP cAMP

Phosphodiesterase

AMP

• Many signal molecules trigger formation of cAMP

• Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases

• cAMP usually activates protein kinase A, which phosphorylates various other proteins

• Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase

First messengerFig. 11-11

G protein

Adenylylcyclase

GTP

ATP

cAMPSecondmessenger

Proteinkinase A

G protein-coupledreceptor

Cellular responses

B. Ca Ions and Inositol Triphosphate (IP3)

• Calcium (Ca2+) is an important second messenger because cells can regulate its concentration

EXTRACELLULARFLUID

Fig. 11-12

ATP

Nucleus

Mitochondrion

Ca2+ pump

Plasmamembrane

CYTOSOL

Ca2+

pumpEndoplasmicreticulum (ER)

Ca2+

pumpATP

Key

High [Ca2+]

Low [Ca2+]

• A signal relayed by a STP may trigger an inc in Ca in cytosol

• Pathways leading to the release of Ca involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers

Fig. 11-13-1

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein

GTP

G protein-coupledreceptor Phospholipase C PIP2

IP3

DAG

(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Fig. 11-13-2

G protein

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein-coupledreceptor Phospholipase C PIP2

DAG

IP3

(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Ca2+

(secondmessenger)

GTP

Fig. 11-13-3

G protein

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein-coupledreceptor Phospholipase C PIP2

DAG

IP3

(second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER) Ca2+

CYTOSOL

Variousproteinsactivated

Cellularresponses

Ca2+

(secondmessenger)

GTP

• Signal Transduction Pathways (Andersen 10min)

X. Nuclear and Cytoplasmic Responses

• Pathway leads to regulation of one or more cellular activities

• Pathways regulate the synthesis of enzymes / proteins, by turning genes on / off in nucleus

• Final molecule may function as a transcription factor

Fig. 11-14

Growth factor

Receptor

Phosphorylationcascade

Reception

Transduction

Activetranscriptionfactor

ResponseP

Inactivetranscriptionfactor

CYTOPLASM

DNA

NUCLEUS mRNA

Gene

• Other pathways regulate the activity of enzymes

Reception

Transduction

Response

Binding of epinephrine to G protein-coupled receptor (1 molecule)

Inactive G protein

Active G protein (102 molecules)

Inactive adenylyl cyclaseActive adenylyl cyclase (102)

ATPCyclic AMP (104)

Inactive protein kinase AActive protein kinase A (104)

Inactive phosphorylase kinase

Active phosphorylase kinase (105)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (106)

GlycogenGlucose-1-phosphate

(108 molecules)

• Signaling pathways can also affect the physical characteristics of a cell, for example, cell shape

Directional Growth in YeastRESULTS

CONCLUSION

Wild-type (shmoos)

∆Fus3

∆formin

Shmoo projection forming Formi

nP

Actinsubunit

P

PFormin

Formin

Fus3

Phosphory- lation cascade

GTP

G protein-coupledreceptor

Matingfactor

GDP

Fus3

Fus3P

Microfilament

XI. Fine-Tuning of the Response

• Multistep pathways have two important benefits:

A. Signal Amplification

• Enzyme cascades amplify the cell’s response

• At each step, the number of activated products is much greater than in the preceding step

B. Specificity and Coordination of the Response

• Different kinds of cells have different collections of proteins

– Allow cells to detect and respond to different signals

• Even the same signal can have different effects in cells with different proteins and pathways

• Pathway branching and “cross-talk” further help the cell coordinate incoming signals

Fig. 11-17a

Signalingmolecule

Receptor

Relaymolecules

Response 1

Cell A. Pathway leadsto a single response.

Cell B. Pathway branches,leading to two responses.

Response 2 Response 3

Fig. 11-17b

Response 4 Response 5

Activationor inhibition

Cell C. Cross-talk occursbetween two pathways.

Cell D. Different receptorleads to a different response.

C. Signaling Efficiency: Scaffolding Proteins

• Scaffolding proteins = large relay proteins to which other relay proteins are attached

– Can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

Fig. 11-18

Signalingmolecule

Receptor

Scaffoldingprotein

Plasmamembrane

Threedifferentproteinkinases

D. Termination of the Signal

• When signal molecules leave the receptor, the receptor reverts to its inactive state

XII. Apoptosis (programmed cell death)

• Apoptosis is programmed or controlled cell suicide

• Cell is chopped and packaged into vesicles that are digested by scavenger cells

• Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells

Fig. 11-19

2 µm

Apoptosis of human white blood cells

Fig. 11-20a

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

Mitochondrion

Ced-4 Ced-3Receptorfor death-signalingmolecule

Inactive proteins

(a) No death signal

Fig. 11-20b

(b) Death signal

Death-signalingmolecule

Ced-9(inactive)

Cellformsblebs

ActiveCed-4

ActiveCed-3

Activationcascade

Otherproteases

Nucleases

XIII. Apoptotic Pathways and Signals

• Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis

• Apoptosis can be triggered by:

– An extracellular death-signaling ligand

– DNA damage in the nucleus

– Protein misfolding in the endoplasmic reticulum

• Apoptosis needed for the development and maintenance of all animals

• Apoptosis may be involved in some diseases (Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers

Fig. 11-21

Interdigital tissue 1 mm

Effect of apoptosis during paw development in the mouse

Overview Cell Communication (Bleier 17 min)