Cell Signaling AP Chapter 11. Evolution of cell signaling Similarities in pathways in bacteria,...
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Transcript of Cell Signaling AP Chapter 11. Evolution of cell signaling Similarities in pathways in bacteria,...
Cell Signaling
AP Chapter 11
Evolution of cell signaling
• Similarities in pathways in bacteria, protists, fungi, plants, and animals suggest an early evolution of signaling pathways
Bacteria communication“bacteria talking to each other”
• Quorum sensing- concentration of signaling molecules allows bacteria to sense their local density
• Ex- Vibrio – glowing bacteria (luciferase enzyme) give off auto inducers into their environment
autoinducers
Quorum sensing can lead to the formation of biofilms
Slime molds – chemical signaling
• Slime molds live as solitary amoebae.• When slime mold cells begin to starve or dehydrate,
they release a pheromone-like chemical called cyclic AMP. This messenger molecule alerts other slime mold amoebae. They detect the cAMP and follow the scent to join forces with the troubled amoebae forming a large mass of cells.
Other slime mold amoebae detect the cAMP and follow the scent to join forces with the troubled amoebae.
cAMP is an important chemical word in the language of cells and seems to be understood and made by all cells, even our own.
Fruiting body formation in fungichemical signaling
Local and long-distance signaling
Direct cytoplasmic connections:
- gap junctions or plasmodesmata in plant cells
- contact of surface molecules (cell-to- cell recognition via receptors
Plasmodesmata in plant cells
Gap junctions in animal cells
Immune cells – direct contact
Local regulators – nearby cells • paracrine signaling – only includes cells
of a particular organ• synaptic signaling – between neurons
• Long distance
• endocrine signaling
• nerve transmission
3 stages of cell signaling
1. Reception
2. Transduction
3. 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
Reception
• Ligand – the signal molecule, fits like a lock and key to receptor
• Most ligands bind to cell surface receptors; some bind to intracellular receptors
• Usually induces a shape change in receptor protein’s shape
Types of receptorsBind with water-soluble molecules on
membrane:
• G-Protein-linked Receptor
• Tyrosine Kinase Receptor
• Ligand-gated Ion Channel
Bind with hydrophobic receptors:
• Intracellular Receptors
G- Protein-Linked Receptors
• 7 protein helices that span the membrane
• Binding of the ligand to the G-protein receptor, activates a specific G protein located on the cytoplasm side. How - GDP becomes GTP.
• The activated G-protein activates a membrane-bound enzyme which continues on its pathway.
• The GTP goes back to GDP.Animation: Membrane-Bound Receptors that Activate G Proteins
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
How important is the G-protein system?
• Used by hormones, neurotransmitters, sensory reception, development….
• Many bacteria produce toxins that interfere with with G-protein systems
• Up to 60% of medicines influence G-protein pathways
Tyrosine kinase receptors• Receptor tyrosine kinases are membrane receptors that attach
phosphates from ATP to tyrosines (Remember kinase…ATP.)
• Once the receptors are activated, relay proteins bind to them and become activated themselves.
• 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
Tyrosine Kinase Receptors
• Binding of the signal molecules causes the two polypeptides to join.
They are activated and act as enzymes to phosphorylate the
tyrosines in the tails.
The receptor protein is now recognized by relay proteins,
triggering different effects.
Ligand-gated ion channel
• A ligand-gated ion channel receptor acts as a gate
• When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor
• Ex- in neurotransmitters and nervous signal transmission
Fig. 11-7d
Signalingmolecule(ligand)
Gateclosed Ions
Ligand-gatedion channel receptor
Plasmamembrane
Gate open
Cellularresponse
Gate closed3
2
1
Ligand-Gated Ion Channels
http://msjensen.cehd.umn.edu/1135/Links/Animations/Flash/0003-swf_receptors_link.swf
Intracellular Receptors
• Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors
• Examples of hydrophobic messengers are the steroid and thyroid hormones of animals
• An activated hormone-receptor complex can act as a transcription factor, turning on specific genes
Fig. 11-8-5
Hormone(testosterone)
EXTRACELLULARFLUID
Receptorprotein
Plasmamembrane
Hormone-receptorcomplex
DNA
mRNA
NUCLEUS New protein
CYTOPLASM
Intracellular Receptors
http://highered.mcgraw-hill.com/olc/dl/120109/bio46.swf
Signal Transduction
• Allow for amplification of signals
• Signal coordination and regulation
• Involves
1) second messengers (cAMP and Ca+2)
2) relay proteins such as protein kinases
How does epinephrine work?...an example of cAMP messenging
• Epinephrine acts via cyclic AMP (cAMP) as a second messenger.
• An activated G protein activates the enzyme adenylyl cyclase (THINK CYCLING!) which turns ATP to cAMP.
• Then cAMP can activate other inactive molecules to reach the desired product.
action of epinephrine Video | DnaTube.com - Scientific Video Site
Adenylyl cyclase
Fig. 11-10
Pyrophosphate
P P i
ATP cAMP
Phosphodiesterase
AMP
First messengerFig. 11-11
G protein
Adenylylcyclase
GTP
ATP
cAMPSecondmessenger
Proteinkinase A
G protein-coupledreceptor
Cellular responses
cAMP second messenger systems
Membrane Structure
• Calcium ions also act as second messengers.
One example is activating an enzyme phospholipase C to produce two more messengers which will open Ca channels.
The signal receptor may be a G protein or a tyrosine kinase receptor.
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
RELAY PROTEINS
• Enzymes called protein kinases are also important links in transduction.
• A protein kinase catalyzes the transfer of PHOSPHATE GROUPS from ATP to another protein to activate it.
• Amplification is possible in these type of pathways.
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
This can get pretty complicated!
Cell Responses
• Alteration of metabolism
• Rearrangement of cytoskeleton
• Modulation of gene activity
Fig. 11-14
Growth factor
Receptor
Phosphorylationcascade
Reception
Transduction
Activetranscriptionfactor
ResponseP
Inactivetranscriptionfactor
CYTOPLASM
DNA
NUCLEUS mRNA
Gene
ModulatingGeneActivity
Fig. 11-15
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)
Alteration ofMetabolism
Fig. 11-16RESULTS
CONCLUSION
Wild-type (shmoos) ∆Fus3 ∆formin
Shmoo projection forming
ForminP
ActinsubunitP
PForminFormin
Fus3
Phosphory- lation cascade
GTP
G protein-coupledreceptor
Matingfactor
GDP
Fus3 Fus3
P
Microfilament
1
2
3
4
5
RearrangementOf cytoskeleton
Fine-Tuning of the Response
• Multistep pathways have two important benefits:– Amplifying the signal (and thus the response)– Contributing to the specificity of the response
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
The Specificity of Cell Signaling and Coordination of the Response
• Different kinds of cells have different collections of proteins which allow cells to detect and respond to different signals.
• Even the same signal can have different effects in cells with different proteins and pathways
Fig. 11-17
Signalingmolecule
Receptor
Relaymolecules
Response 1
Cell A. Pathway leadsto a single response.
Response 2 Response 3
Cell B. Pathway branches,leading to two responses.
Response 4 Response 5
Activationor inhibition
Cell C. Cross-talk occursbetween two pathways.
Cell D. Different receptorleads to a different response.
Pathway branching and “cross-talk” further help the cell coordinate incoming signals
Same signal - different effects in cells with different proteins and pathways
Signaling Efficiency: Scaffolding Proteins and Signaling Complexes
• Scaffolding proteins are large relay proteins to which other relay proteins are attached
• Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway
Fig. 11-18
Signalingmolecule
Receptor
Scaffoldingprotein
Plasmamembrane
Threedifferentproteinkinases
Apoptosis (programmed cell death) integrates multiple cell-signaling pathways
• Apoptosis is programmed or controlled cell suicide
• A 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
• Apoptosis is important in shaping an organism during embryonic development
Fig. 11-20b
(b) Death signal
Death-signalingmolecule
Ced-9(inactive)
Cellformsblebs
ActiveCed-4
ActiveCed-3
Activationcascade
Otherproteases
Nucleases
Apoptotic Pathways and the Signals That Trigger Them
• 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
• 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
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 11-21
Interdigital tissue 1 mm