Cell Signaling: Communication between cells
Three Stages
05-03-16 Lecture 10
Cell Signaling
Receiving Environmental Signals
•Transporters, channels that transport signal across the membrane
•Receptors bind signals endocytosis
•Receptors :•Mediate cell-cell recognition : tight junctions•ECM - adhesion receptors•Signal receivers
Local and Long-Distance Signaling
•Local Signals: •Paracrine – secreted signal from a neighboring cell. Only nearby cells have receptors – and can respond
•Ex. development, histamines
•Autocrine – signals affect the same cells that make it
05-03-16 Lecture 10
Cell Signaling
Local and Long-Distance Signaling
•Long Distance: •Hormonal (produced by glands): small protein (ex. Insulin) or small molecules that circulate via the bloods
Signals are recognized by specific receptors on outside the cell HOW?
•Interactions with side chain (R-groups) on amino acids
•Sends signal inside cell •Growth
•Replicate DNA and divide
•DIE (Apoptosis)•Programmed cell death – turn on proteases in cell
•Turn on genes to do new things
•Change Metabolism•Create new strutures•Make a different signal – new response
05-03-16 Lecture 10
Cell Signaling
Intracellular Receptors
•Steriods
•cross the plasma membrane and bind nuclear receptors in cytoplasm
•Transported into nuclues through nuclear pore complex
•Turn on genes
Hormone(testosterone)
EXTRACELLULARFLUID
Receptorprotein
DNA
mRNA
NUCLEUS
CYTOPLASM
Plasmamembrane
Hormone-receptorcomplex
New protein
Figure 11.6
hydrophobic - can cross PM
NOTE: Proteins that can enter the nucleus have signals (nuclear import signals).
05-03-16 Lecture 10
Cell Signaling
Three stages of Cell Signaling
•Reception:•signal binds protein receptor on cell causes conformational change signals across membrane.
•Transduction:•Amplify the original signal
•Phosphorylation Cascade•Kinase transfers phosphate from ATP to Proteins
•Serine , Threonine, or Tyrosine•Adds a negative charge onto protein•Causes conformation change•Amplify by phosphorylating many other proteins
•Second Messenger System•Turn on a enzyme•Synthesizes a small molecule•Small molecule acts as a “messenger”
•Binds and allosterically activates “turns on” other proteins
Turn protein on!
05-03-16 Lecture 10
Cell Signaling
Three stages of Cell Signaling
•Response:•Change an activity in nucleus by turning genes on
•Change an activity in cytoplasm•Enzyme turned on•Change cytoskeleton
•Open a channel (e.g. brain)
•Opposite can be true also – turn things off•Receive signal•Amplification•Response: unique (specific) to turn a response off!
Examples
05-03-16 Lecture 10
Cell Signaling
Phosphorylation: Why is it important in signaling?
OHSerineThreonineTyrosine
+ HO P
O
O-
O-
from ATP
H20
Enzyme(Kinase)
O P
O
O-
O-
Big charge changeUsed as a ON/OFF Signal
05-03-16 Lecture 10
Cell Signaling
Three main types of membrane receptors
•Tyrosine Kinases
•G-protein linked
•Ion channels
05-03-16 Lecture 10
Cell Signaling
Tyrosine Kinase receptors
•Transmembrane protein•ligand binds outside surface of cell•Activates kinase inside cell
•Note: inactive without ligand
•Binds ligand conformational change•3˚ 4˚•Mononer dimer•(inactive) (active)
•Kinase phosphorylates many substrates including itself
•Response: ex. turn genes on (development)•Growth hormones use this strategy – signal to divide
To turn OFF: use a phosphatase – removes phosphates from proteins!
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Signalmolecule
Signal-binding sitea
CYTOPLASM
Tyrosines
Signal molecule
TyrTyrTyr
TyrTyr
TyrTyrTyrTyr
TyrTyr
Tyr
TyrTyrTyr
TyrTyr
Tyr TyrTyrTyr
TyrTyr
Tyr
TyrTyrTyr
TyrTyr
Tyr
DimerReceptor tyrosinekinase proteins(inactive monomers)
PPP
PP
P Tyr
TyrTyr
TyrTyr
TyrP
PP
PP
PCellularresponse 1
Inactiverelay proteins
Activatedrelay proteins
Cellularresponse 2
Activated tyrosine-kinase regions(unphosphorylateddimer)
Fully activated receptortyrosine-kinase(phosphorylateddimer)
6 ATP 6 ADP
Figure 11.7
Cell Signaling
Tyrosine Kinase receptors – a schematic
05-03-16 Lecture 10
Cell SignalingCell Signaling
G-protein coupled receptors
•Seven Transmembrane passing protein•Ligand binds outside surface of cell•Binds ligand conformational change•Can now bind “G-protein” insides on membrane
•G-Protein•Able to bind activated G-protein linked receptors•Able to bind GTP
G-protein
GTP
G-protein
GDP
GTP GDP
PiGTP Hydrolysis
05-03-16 Lecture 10
Cell Signaling
G-protein coupled receptors
G-protein-linkedReceptor
Plasma Membrane
EnzymeG-protein(inactive)CYTOPLASM
Cellular response
Activatedenzyme
ActivatedReceptor
Signal moleculeInctivateenzyme
Segment thatinteracts withG proteins
GDP
GDP
GTP
GTP
P i
Signal-binding site
Figure 11.7
GDP
Turn off by hydrolyzing GTP to GDP
05-03-16 Lecture 10
Cell Signaling
ION Channels
•Transmembrane protein (usually a pore or channel)•Closed , waiting for signal•Ligand binds outside surface of cell (neurotransmitter – secreted by neurons)•Binds ligand conformational change•Opens channel for ion (e.g. Na+) to go thru from High to low concentration
•FACLITATED DIFFUSION
•ACTION POTENTIAL – dramatic change in membrane potential (depolarization) due to the rapid influx of Na+ ions!!
•Turns Off: once channel opens and neurotransmitter released and either digested or reabsorbed
05-03-16 Lecture 10
Cellularresponse
Gate open
Gate close
Ligand-gatedion channel receptor
Plasma Membrane
Signalmolecule(ligand)
Figure 11.7
Gate closed Ions
Cell Signaling
ION Channels
ACTION Potential
05-03-16 Lecture 10
Cell Signaling
Phosphorylation Cascade
Signal molecule
Activeproteinkinase
1
Activeproteinkinase
2
Activeproteinkinase
3
Inactiveprotein kinase
1
Inactiveprotein kinase
2
Inactiveprotein kinase
3
Inactiveprotein
Activeprotein
Cellularresponse
Receptor
P
P
P
ATPADP
ADP
ADP
ATP
ATP
PP
PP
PP
Activated relaymolecule
iP
P
i
i
P
Widely used by cells
05-03-16 Lecture 10
Cell Signaling
Second Messenger Signaling
•Cyclic adenosine monophosphate (cAMP)•Produced via G-protein coupled receptor signaling
•Ca2+ influx into the cell•Via channel opening (classic and very important example – ION Channels – via ACTION Potential)
05-03-16 Lecture 10
Cell Signaling
cAMP – a simplified view
ATP
GTP
cAMP
Proteinkinase A
Cellular responses
G-protein-linkedreceptor
AdenylylcyclaseG protein
First messenger(signal moleculesuch as epinephrine)
05-03-16 Lecture 10
Cell Signaling
EXTRACELLULAR
FLUIDPlasma
membrane
ATP
CYTOSOL
ATP Ca2+
pump
Ca2+
pump
Ca2+
pump
Endoplasmic
reticulum (ER)
Nucleus
Mitochondrion
Key High [Ca2+] Low [Ca2+]
Figure 11.11
Ca2+ :
ACTION Potential
Action potential causes Ca2+
to enter cell from outside and from intracellular stores
ON/OFF switch for other proteins
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Cell Signaling – SPECIFITY!
•Many different types of cells•Many signals•Many proteins involved•Many, many responses
•How does the cell accomplish all this?
05-03-16 Lecture 10
Cell Signaling – SPECIFITY!
Response 1
Response 4 Response 5
Response
2
Response
3
Signalmolecule
Cell A. Pathway leads to a single response
Cell B. Pathway branches, leading to two responses
Cell C. Cross-talk occurs between two pathways
Cell D. Different receptorleads to a different response
Activationor inhibition
Receptor
Relaymolecules
Figure 11.15
05-03-16 Lecture 10
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