Chapter 11 Cell Communication. I. Evolution of Cell Signaling Signal transduction pathway = steps by...
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Transcript of Chapter 11 Cell Communication. I. Evolution of Cell Signaling Signal transduction pathway = steps by...
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)