cell-cell communication. overview: cellular signaling cells communicate with each other via chemical...

Cell-Cell Communication

Overview: Cellular Signaling

• Cells communicate with each other via chemical signals.

• For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine

• Cell-to-cell communication is essential for both multicellular and unicellular organisms

• Biologists have discovered some universal mechanisms of cellular communication

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Cell Signaling by Multicellular Organisms

• Coordinates activities within individual cells to support the function of the organism as a whole

• Examples:– Response to DNA damage

• Could lead to expression of mutant proteins and cellular dysfunction and/or cancer if unchecked

• Cell signaling pathways prevent this by activating DNA repair enzymes or initiating programmed cell death (apoptosis)

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Local Signaling

• In local signaling, cells within multicellular organisms may communicate by:– contact through the cytoplasm of adjacent cells

• cell junctions– cell-cell contact

• Ligand on one cell binds to a receptor on an adjacent cell

– short range signals • Cell secretes a soluble ligand that binds to a receptor

on a nearby cell

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Local Signaling:Cytoplasmic contact at cell junctions

Cell-cell contact between adjacent cells involving membrane bound ligands

Local signaling

Target cell

Secretingcell

Secretoryvesicle

Local regulatordiffuses throughextracellular fluid.

(a) Paracrine signaling (b) Synaptic signaling

Electrical signalalong nerve celltriggers release ofneurotransmitter.

Neurotransmitter diffuses across synapse.

Target cellis stimulated.

Short range signals involving soluble ligands

Long-Distance Signaling

• In long distance signaling, cells within multicellular organisms may communicate use chemicals called hormones– synthesized by cells in one region of the body– travel through the bloodstream to reach their

cellular targets in other regions of the body

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Figure 11.5b

Long-distance signaling

Endocrine cell Bloodvessel

Hormone travelsin bloodstream.

Target cellspecificallybinds hormone.

(c) Endocrine (hormonal) signaling

• Only the signaling molecule that fits the shape of a specific receptor can trigger a response in a cell

• Mediated by shape and chemical nature of interacting regions

• Different cell types produce different receptors• A cell synthesizes many different kinds of receptors,

depending on conditions or stages in its life cycle• The same signal can have different meanings for

various target cells

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Signal Specificity and Cell Specialization

The Three Stages of Cell Signaling: (within 1 cell)

1) Reception2) Transduction3) Response

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Figure 11.6-1

Plasma membraneEXTRACELLULARFLUID

CYTOPLASM

Reception

Receptor

Signalingmolecule

1

Figure 11.6-2

Plasma membraneEXTRACELLULARFLUID

CYTOPLASM

Reception Transduction

Receptor

Signalingmolecule

Relay molecules in a signal transductionpathway

21

Figure 11.6-3

Plasma membraneEXTRACELLULARFLUID

CYTOPLASM

Reception Transduction Response

Receptor

Signalingmolecule

Activationof cellularresponse

Relay molecules in a signal transductionpathway

321

Step 1: Signal Reception

• A signaling molecule binds to a receptor protein, causing it to change shape, and initiating the transduction of the signal

• Most receptors are plasma membrane proteins but some are inside of the cell (cytoplasmic/nuclear receptors)

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

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Cell Surface and Intracellular Receptors

Receptors in the Plasma Membrane

• There are three main types of membrane receptors

– Ion channel receptors– G protein-coupled (linked) receptors– Protein kinase receptors (aka receptor

tyrosine kinases)

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• A ligand-gated ion channel receptor acts as a gate

• When a ligand binds to the receptor, the shape changes, allowing specific ions, such as Na+ or Ca2+, to pass into the cell through a channel in the receptor

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Ligand-Gated Ion Channel Receptors

Fig. 6-5a, p. 140

Signaling molecule

Extracellular fluidNa+

Receptor

Cytosol

Ion channel is closed.1 2 When signaling molecule binds to receptor, the channel changes shape and opens. Sodium ions enter the cell.

Ligand-Gated Ion Channel Receptors

• A GPCR is a plasma membrane receptor that works with the help of a G protein, located in the cytoplasm

• Upon ligand binding the G protein is turned on by the exchange of GDP for GTP

• The G protein then helps to transmit the intracellular signal

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G Protein Linked Receptors

Fig. 6-5b, p. 140

Signaling molecule

Receptor

G protein Enzyme

CytosolGDP GTP

Inactive state: the three subunits of G protein are joined and it is bound to GDP

1 2 Ligand binding: receptor binds to G protein causing GDP to be replaced with GTP and the separation of one subunit. This is the active state.

G Protein Coupled Receptors

• PKRs are membrane receptors that also have enzymatic activity

• transfer phosphate groups (phosphorylation) from ATP to specific tyrosine residues on proteins

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

• Abnormal functioning of PKRs is associated with many types of cancers

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Protein Kinase Receptors

Signalingmolecule (ligand)

21

3 4

Ligand-binding site

helix in themembrane

Tyrosines

CYTOPLASM Receptor tyrosinekinase proteins(inactive monomers)

Signalingmolecule

Dimer

Tyr

TyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

TyrTyrTyr

P

PP

PPP

P

PP

P

PP

Activated tyrosinekinase regions(unphosphorylateddimer)

Fully activatedreceptor tyrosinekinase(phosphorylateddimer)

Activated relayproteins

Cellularresponse 1

Cellularresponse 2

Inactiverelay proteins

6 ATP 6 ADP

Receptor Tyrosine Kinases

Intracellular Receptors

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• Intracellular receptors are found in the cytosol or nucleus – most are transcription factors that regulate expression of specific genes

• Signaling molecules are small, hydrophobic molecules that diffuse across the membranes of target cells– Some combine with receptors in the cytosol, then move

into the nucleus (e.g. steroid hormones)– Some bind to receptors already bound to DNA inside

the nucleus (e.g. thyroid hormones)

Hormone(testosterone)

Receptorprotein

Plasmamembrane

EXTRACELLULARFLUID

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS

CYTOPLASM

New protein

Steroid hormone interacting with an intracellular receptor

Step 2: Signal Transduction

• Cascades of molecular interactions relay signals from receptors to target molecules in the cell.

• Signals are relayed by:– Protein kinases – Second messengers

• Both of these mechanisms help to amplify the signal inside of the cell

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Step 2: Signal Transduction• Protein kinases help to transmit signals

through a cascade of protein phosphorylations– Protein kinases transfer phosphate groups from

ATP to other proteins, a process called phosphorylation

• acts like a molecular on-off switch– The addition of phosphate groups (by

kinases)acts like an “on” switch and activates proteins

– The removal of phosphate groups (by phosphatases) acts like an “off” switch and de-activates proteins

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Receptor

Signaling molecule

Activated relaymolecule

Phosphorylation cascade

Inactiveprotein kinase

1 Activeprotein kinase

1

Activeprotein kinase

2

Activeprotein kinase

3

Inactiveprotein kinase

2

Inactiveprotein kinase

3

Inactiveprotein

Activeprotein

Cellularresponse

ATPADP

ATPADP

ATPADP

PP

PP

PP

P

P

P

P i

P i

P i

Figure 11.10

Signal transduction by protein kinases involving a phosphorylation cascade

Step 2: Signal Transduction

• Second messengers– Ions or small molecules that amplify signals

inside the cell and relay them to other signaling or target proteins

– Ex: cyclic AMP (cAMP), inositol triphosphate (IP3) , and calcium ions (Ca2+)

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Fig. 6-7, p. 143

Signaling molecule (first messenger)

Extracellular fluid

Adenylyl cyclaseReceptor G protein

Plasma membrane

Cytosol

cAMP

cAMP cAMP cAMP Second messenger

Protein Protein Protein

Alters metabolism

Affects gene activity

Opens or closes ion channels

1

2

3

Ligand binds to GPCR, activating the G protein and causing one subunit to bind to and activate Adenylyl Cyclase, which then catalyzes formation of cAMP from ATP

Signal is amplified and relayed by the second messenger cAMP

Response: some cell process is altered

Figure 11.14-3

G protein

EXTRA-CELLULARFLUID

Signaling molecule(first messenger)

G protein-coupledreceptor Phospholipase C

DAG

PIP2

IP3 (second messenger)

IP3-gatedcalcium channel

Endoplasmicreticulum (ER)

CYTOSOL

Variousproteinsactivated

Cellularresponses

Ca2

(secondmessenger)

Ca2

GTP

Signaling pathway involvingthe second messengers

IP3 and Ca2

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

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Signal Amplification

Step 3: ResponseCell signaling leads to regulation of cellular activity including:•Opening or closing of ion channels •Alteration of enzyme activity, leading to metabolic changes

• Ex, fight or flight response•Alteration of specific gene activity

• specific proteins made or not made in response •Apoptosis

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Cellular Response to Signaling

Growth factor

ReceptorReception

Transduction

CYTOPLASM

Response

Inactivetranscriptionfactor

Activetranscriptionfactor

DNA

NUCLEUS mRNA

Gene

Phosphorylationcascade

P

Cellular Response:

Activation of a

specific gene by a

growth factor

Termination of the Signal

• Inactivation mechanisms are an essential aspect of cell signaling

• If ligand concentration falls, fewer receptors will be bound

• Unbound receptors revert to an inactive state

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How does cell signaling trigger the desperate flight of this gazelle?

Link

• Epinephrine (adrenaline), a hormone, is released by the adrenal gland.

• It travels through the blood stream to reach its target in muscle or liver cells.

• There is binds to a G protein coupled receptor and initiates a signaling cascade

• Results in glucose release by the cells leading to increased heart and breathing rate

Fight or Flight Signaling Pathway

Fig. 6-9a, p. 144

EpinephrineExtracellular fluid

G protein

Adenylyl cyclase

G protein coupled receptor

Plasma membrane

Cytosol

1

Fight or Flight Signaling Pathway

Reception of Signal

Fig. 6-9b, p. 144

EpinephrineG protein coupled receptor G protein

separatesAdenylyl cyclase

2

Fight or Flight Signaling Pathway

Initiation of Signal Transduction

Fig. 6-9c, p. 144

Adenylyl cyclase activated

G protein coupled Receptor

Phosphorylated Protein kinase A

Phosphorylated protein (active)

Protein

Glycogen is broken down into glucose, which is released by the cell. Causes increased blood flow and heart rate as well as increased breathing rate.

3

Ligand: epinephrine

Dissociation of activated G protein

Fight or Flight Signaling Pathway

Cellular Response

Animation

Apoptosis integrates multiple cell-signaling pathways

• Apoptosis is programmed or controlled cell suicide

• Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells

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

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• Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals

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

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Role of Apoptosis in Development and Disease

Figure 11.22

Interdigital tissueCells undergoing

apoptosisSpace between

digits1 mm

Role of Apoptosis in Development

Evolutionary History of Cell Signaling• Similarities in cell communication among diverse

organisms suggest that the molecules and mechanisms used in information transfer evolved long ago

• Evidence suggests that cell communication first evolved in prokaryotes– Some signal transduction pathways found in organisms

as diverse as yeasts and animals are quite similar– Highly conserved nature suggests an evolutionary

relationship

Cellular Signaling and Development

• Cellular signaling plays a critical role in development and maintenance of multicellular organisms– establishment of body axes– cell fate decisions leading to the formation of

germ layers and organ development– maintenance of stem cells within the body

Cellular Signaling and Disease

• Mutations that cause over- or underactive cell signaling can result in disease– diabetes, neurological diseases, autoimmune

diseases, cancer• Many therapeutic drugs seek to block or

balance out over- or underactive signaling pathways– birth control, antihistamines, anti-psychotics,

anti-cancer drugs

Cellular Signaling and Biotechnology

• Understanding these pathways allows scientists to modify or manipulate biological systems and cellular physiology– Drugs to treat disease– Control of fruit ripening – Use of growth hormones in poultry, etc– Doping by athletes (EPO, HGH)

Helpful Videos/Animations:• AP Biology Hayescience “Cell Communication” a general overview- can go back to look at

specifics https://www.youtube.com/watch?v=XtN9YjIJhz8

• Crash Course “Nervous System Part 3: Synapses” a general overview https://www.youtube.com/watch?v=VitFvNvRIIY

• Bozeman “Cell Communication” https://www.youtube.com/watch?v=xnGXItWrJ3k

• Bozeman “Signal Transduction Pathways” https://www.youtube.com/watch?v=qOVkedxDqQo

• Life (your textbook): Ch. 7 animations - “Signal Transduction Pathway” & “Signal Transduction & Cancer” http://bcs.whfreeman.com/thelifewire9e/default.asp#542578__591101__

• The Penguin Prof “Signal Transduction” https://www.youtube.com/watch?v=pH_ibPHK0y0

• Learn Genetics “Fight or Flight Response” example of Signal Transduction http://learn.genetics.utah.edu/content/cells/cellcom/

SEE ALSO THE CELL SIGNALING WEBQUEST ACTIVITY FOR ADDITIONAL SPECIFIC SUPPORT VIDEOS/ANIMATIONS.

Cell Signaling by Single Celled Organisms

• Influences how they respond to the environment• Examples:

– Quorum sensing in bacteria• Send and receive signaling relaying info on

population density• When few organisms present little signaling• As numbers increase, more signaling, which can result

in different cellular outcomes

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Cell Signaling by Single Celled Organisms

– Quorum sensing in bacteria• Pseudomonas aerginosa live in host without harm until

reach a certain population density

• At high density they form a biofilm and cell signaling changes their gene expression to start producing toxins

– Biofilm: A community of microorganisms attached to a solid surface; requires the coordinated activity of numerous bacteria

• Results in host pathology

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Cell Signaling by Single Celled Organisms– Quorum sensing in Pseudomonas aerginosa

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Cell Signaling by Single Celled Organisms

– Quorum sensing in bacteria• Vibrio fischeri is a bioluminescent bacteria that lives in a

mutualistic relationship within the light producing organ of a Hawaiian squid

• In low numbers and with low signaling, bacteria do not synthesize the light producing protein

• In high numbers and with high signaling, bacteria do synthesize the light producing protein

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Cell Signaling by Single Celled Organisms– Quorum sensing in Vibrio fischeri

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