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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) © 2011 Pearson Education, Inc.
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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
© 2011 Pearson Education, Inc.
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)
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Signal Specificity and Cell Specialization
The Three Stages of Cell Signaling: (within 1 cell)
1) Reception2) Transduction3) Response
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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)
© 2011 Pearson Education, Inc.
• 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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
• 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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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+)
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
• 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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Cell Signaling by Single Celled Organisms– Quorum sensing in Pseudomonas aerginosa
© 2011 Pearson Education, Inc.
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
© 2011 Pearson Education, Inc.
Cell Signaling by Single Celled Organisms– Quorum sensing in Vibrio fischeri
© 2011 Pearson Education, Inc.