cell signaling i
DESCRIPTION
Cell signalingTRANSCRIPT
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A Simple Intracellular Signaling Pathway Activated by an Extracellular Signal Molecule
Figure 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015). 1
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Characteristics of Extracellular Signaling Molecules Secreted from a signaling cell Peptides, amino acids nucleotides steroids retinoids, fatty acid derivatives, dissolved gases Released into extracellular space by exocytosis or diffusion
Characteristics of Receptor Proteins Target cell responds by means of a receptor Receptors are usually on the surface of the target cell (but can be found
inside the cell) Often a transmembrane protein Binds extracellular signal molecule with high affinity Upon binding the signaling molecule (ligand), the receptor *activates* a series of intracellular signals that alters cell behavior.
2
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Forms of Intercellular Signaling
Extracellular signal molecules can act over either short or long distances Signaling and target cells are usually distinct cell types
Figure 15-2. Molecular Biology of the Cell 6e ( Garland Science, 2015). 3
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The Binding of Extracellular Signal Molecules to Either Cell-Surface or Intracellular Receptors
(water soluble)
(Diffuses through lipid bilayer)
Most signal molecules are hydrophilic and unable to cross the plasma membrane of the target cell. They bind to cell surface receptors, which generate intracellular signals within the target.
Figure 15-3. Molecular Biology of the Cell 6e ( Garland Science, 2015). 4
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Cells Depend on Multiple Extracellular Signals
Specific combinations of signaling molecules can regulate cell behavior
programmed
cell death
Figure 15-4. Molecular Biology of the Cell 6e ( Garland Science, 2015). 5
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Figure 15-5. Molecular Biology of the Cell 6e (Garland Science, 2015).
Various Responses Induced by the Neurotransmitter Acetylcholine A B C D
Signal molecules differentially affect distinct target cells. The effect of a signal molecule on a cell is regulated by the intracellular molecules which respond to the receptor, downstream effector proteins and genes activated. These are dictated by the cells predetermined state which depends on the cells developmental history.
6
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Three Classes of Cell-Surface Receptors
Protein lined channel through the membrane
receptor = channel protein
Receptor is a 7 pass transmembrane protein which activates a membrane bound (usually trimeric) GTPase (G-protein)
Single pass receptor is an enzyme or binds directly to an enzyme
Figure 15-6. Molecular Biology of the Cell 6e (Garland Science, 2015).
A) Ion Channel-Coupled Receptors
B) G-Protein-Coupled Receptors
C) Enzyme-Coupled Receptors
7
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Two Types of Intracellular Signaling Proteins That Act as Molecular Switches
-proteins activated or inactivated by phosphorylation
Kinase
(ser/thr
or tyr)
phosphatase
GTPase Intrinsic GTPase activity
Figure 15-7. Molecular Biology of the Cell 6e (Garland Science, 2015).
-activated by GTP -monomeric trimeric
Cell Surface Receptors Relay Signals Via Intracellular Signaling Molecules
8
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Three Types of Intracellular Signaling Complexes
Scaffold proteins serve as a strategy for enhancing specificity of interactions between signaling molecules by localizing them.
organize groups of interacting signaling proteins into signaling complexes
ensure they interact with each other and not with inappropriate partners.
increase local concentrations
speed
efficiency
decreases cross talk with other signaling pathways
A
B
C
Figure 15-10. Molecular Biology of the Cell 6e (Garland Science, 2015). 9
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Modular interaction domains mediate interactions between intracellular signaling proteins
Figure 15-11. Molecular Biology of the Cell 6e (Garland Science, 2015).
activated insulin receptor
(insulin receptor substrate) -small interaction domains found in many signaling proteins -bind structural motifs found in other proteins and lipids
10
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Molecular Interaction Domains Allow Assembly of Signal Complex
PTB - Phosphotyrosine binding SH2 - Src homology 2 binds phosphorylated tyrosine within a particular peptide sequence
SH3 - Src homology 3 binds proline-rich sequences
PH - Pleckstrin Homology - binds phosphoinositides to enable membrane docking
Adaptor - link proteins together through 2 or more interaction
Protein domains Chains or - signaling molecules assemble into complexes to Branching form chains and branching networks which cluster Networks in the lipid bilayer (rafts) of plasma membrane
11
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Some Ways in Which Target Cells Can Become Adapted (Desensitized) to an Extracellular Signal Molecule
Adaptation of target cells to high levels of signaling proteins
Adjust sensitivity to signal
internalization internalization & degradation
in appropriate phosphorylation
Figure 15-20. Molecular Biology of the Cell 6e (Garland Science, 2015). 12
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Activation of a G protein by an activated GPCR
Figure 15-23. Molecular Biology of the Cell 6e (Garland Science, 2015).
GPCRs large family of receptors which mediate cellular responses to extracellular signals -signal polypeptide chain which passes through the membrane 7 times -function through G-proteins to transmit signals -half of all known drugs work through GPCRs or their signaling pathways
Signaling through G-protein Coupled Receptors
ligand bound GPCR binds to and activates G-protein by triggering the exchange of GDP for GTP -GTP bound G-protein activates effector proteins such as the membrane-bound enzyme adenylate cyclase Adenylate cyclase Cyclic AMP (cAMP) GPCRs linked to a stimulatory G-protein (Gs) activate adenylate cyclase inhibitory G-protein (Gi) inhibit adenylate cyclase
13
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The Synthesis and Degradation of Cyclic AMP
Figure 15-25. Molecular Biology of the Cell 6e (Garland Science, 2015).
cAMP functions as a second messenger to activate cAMP-dependent enzymes in the cytosol, mainly cAMP dependent protein kinase A (PKA). PKA phosphoroylates ser-thr residues on target proteins
14
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The Activation of Cyclic-AMP-Dependent Protein Kinase (PKA)
Figure 15-26. Molecular Biology of the Cell 6e (Garland Science, 2015).
controls activity and subcellular localization
15
-
Figure 15-27. Molecular Biology of the Cell 6e (Garland Science, 2015).
How a Rise in Intracellular Cyclic AMP Concentration Can Alter Gene Transcription
16
-
Table 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).
Some Hormone-Induced Cell Responses Mediated by Cyclic AMP
17
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The Hydrolysis of PI(4,5) P2 by Phospholipase C-
Figure 15-28. Molecular Biology of the Cell 6e ( Garland Science, 2015).
G-protein Signaling Through Phospholipids
(DAG) DAG and Ca2+ are considered second messengers
18
-
How GPCRs Increase Cytosolic Ca2+ and Activate Protein Kinase C
Figure 15-29. Molecular Biology of the Cell 6e (Garland Science, 2015).
Ca2+ is an effective signaling mediator because its cytosolic concentration is low (10-7M), whereas extracellular and lumen concentrations are high (10-3M). Ca2+ pumps in plasma and ER membranes drive Ca2+ out of the cell into the ER to lower cytosolic concentrations and terminate Ca2+ signaling.
19
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The Structure of Ca2+/Calmodulin
Figure 15-33. Molecular Biology of the Cell 6e (Garland Science, 2015).
Calmodulin is a Ca2+ binding protein which binds to and activates enzymes. Serves as a Ca2+ dependent regulatory subunit in many enzyme complexes. This family of enzymes is Ca2+/calmodulin-dependent kinases (CaM-kinases). They phosphorylate a variety of target proteins.
20
-
Some Cell Responses in Which GPCRs Activate PLC
Table 15-2. Molecular Biology of the Cell 6e (Garland Science, 2015). 21
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A Simple Intracellular Signaling Pathway Activated by an Extracellular Signal Molecule
Figure 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).
*
Characteristics of Extracellular Signaling MoleculesSecreted from a signaling cellPeptides, amino acids nucleotides steroids retinoids, fatty acid derivatives, dissolved gases
Released into extracellular space by exocytosis or diffusion
Characteristics of Receptor ProteinsTarget cell responds by means of a receptor
Receptors are usually on the surface of the target cell (but can be found inside the cell)
Often a transmembrane protein
Binds extracellular signal molecule with high affinity
Upon binding the signaling molecule (ligand), the receptor *activates* a series of intracellular signals that alters cell behavior.
*
Forms of Intercellular Signaling
Extracellular signal molecules can act over either short or long distancesSignaling and target cells are usually distinct cell types
Figure 15-2. Molecular Biology of the Cell 6e ( Garland Science, 2015).
*
The Binding of Extracellular Signal Molecules to Either Cell-Surface or Intracellular Receptors
(water soluble)
(Diffuses through lipid bilayer)
Most signal molecules are hydrophilic and unable to cross the plasma membrane of the target cell. They bind to cell surface receptors, which generate intracellular signals within the target.
Figure 15-3. Molecular Biology of the Cell 6e ( Garland Science, 2015).
*
Cells Depend on Multiple Extracellular Signals
Specific combinations of signaling molecules can regulate cell behavior
Figure 15-4. Molecular Biology of the Cell 6e ( Garland Science, 2015).
*
Figure 15-5. Molecular Biology of the Cell 6e (Garland Science, 2015).
Various Responses Induced by the Neurotransmitter Acetylcholine
A
B
C
D
Signal molecules differentially affect distinct target cells. The effect of a signal molecule on a cell is regulated by the intracellular molecules which respond to the receptor, downstream effector proteins and genes activated. These are dictated by the cells predetermined state which depends on the cells developmental history.
*
Three Classes of Cell-Surface Receptors
Protein lined channel through the membrane receptor = channel protein
Receptor is a 7 passtransmembrane protein which activates a membrane bound (usually trimeric) GTPase (G-protein)
Single pass receptor is an enzyme or binds directly to an enzyme
Figure 15-6. Molecular Biology of the Cell 6e (Garland Science, 2015).
A) Ion Channel-Coupled Receptors
B) G-Protein-Coupled Receptors
C) Enzyme-Coupled Receptors
*
Two Types of Intracellular Signaling Proteins That Act as Molecular Switches
-proteins activated or inactivated by phosphorylation
Kinase(ser/thr or tyr)
phosphatase
GTPase Intrinsic GTPase activity
Figure 15-7. Molecular Biology of the Cell 6e (Garland Science, 2015).
-activated by GTP-monomeric trimeric
Cell Surface Receptors Relay Signals Via Intracellular Signaling Molecules
*
Three Types of Intracellular Signaling Complexes
Scaffold proteins serve as a strategy for enhancing specificity of interactions between signaling molecules by localizing them.organize groups of interacting signaling proteins into signaling complexesensure they interact with each other and not with inappropriate partners. increase local concentrations speed efficiency decreases cross talk with other signaling pathways
A
B
C
Figure 15-10. Molecular Biology of the Cell 6e (Garland Science, 2015).
*
Modular interaction domains mediate interactionsbetween intracellular signaling proteins
Figure 15-11. Molecular Biology of the Cell 6e (Garland Science, 2015).
activated insulin receptor
(insulin receptor substrate)
-small interaction domains found in many signaling proteins-bind structural motifs found in other proteins and lipids
*
Molecular Interaction Domains Allow Assembly of Signal Complex
PTB-Phosphotyrosine binding
SH2-Src homology 2 binds phosphorylated tyrosine within a particular peptide sequence
SH3-Src homology 3 binds proline-rich sequences
PH-Pleckstrin Homology - binds phosphoinositides toenable membrane docking
Adaptor-link proteins together through 2 or more interaction Proteindomains
Chains or -signaling molecules assemble into complexes to Branchingform chains and branching networks which cluster Networksin the lipid bilayer (rafts) of plasma membrane
*
Some Ways in Which Target Cells Can Become Adapted (Desensitized) to an Extracellular Signal Molecule
Adaptation of target cells to high levels of signaling proteins Adjust sensitivity to signal
internalization
internalization °radation
in appropriate phosphorylation
Figure 15-20. Molecular Biology of the Cell 6e (Garland Science, 2015).
*
Activation of a G protein by an activated GPCR
Figure 15-23. Molecular Biology of the Cell 6e (Garland Science, 2015).
GPCRs
large family of receptors which mediate cellular responses to extracellular signals
-signal polypeptide chain which passes through the membrane 7 times
-function through G-proteins to transmit signals
-half of all known drugs work through GPCRs or their signaling pathways
Signaling through G-protein Coupled Receptors
*
The Synthesis and Degradation of Cyclic AMP
Figure 15-25. Molecular Biology of the Cell 6e (Garland Science, 2015).
cAMP functions as a second messenger to activate cAMP-dependent enzymes in the cytosol, mainly cAMP dependent protein kinase A (PKA).
PKA phosphoroylates ser-thr residues on target proteins
*
The Activation of Cyclic-AMP-Dependent Protein Kinase (PKA)
Figure 15-26. Molecular Biology of the Cell 6e (Garland Science, 2015).
controls activity and subcellular localization
*
Figure 15-27. Molecular Biology of the Cell 6e (Garland Science, 2015).
How a Rise in Intracellular CyclicAMP Concentration Can Alter Gene Transcription
*
Table 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).
Some Hormone-Induced Cell Responses Mediated by Cyclic AMP
*
The Hydrolysis of PI(4,5) P2 by Phospholipase C-
Figure 15-28. Molecular Biology of the Cell 6e ( Garland Science, 2015).
G-protein Signaling Through Phospholipids
(DAG)
DAG and Ca2+ are considered second messengers
*
How GPCRs Increase Cytosolic Ca2+ and Activate Protein Kinase C
Figure 15-29. Molecular Biology of the Cell 6e (Garland Science, 2015).
Ca2+ is an effective signaling mediator because its cytosolic concentration is low (10-7M), whereas extracellular and lumen concentrations are high (10-3M).
Ca2+ pumps in plasma and ER membranes drive Ca2+ out of the cell into the ER to lower cytosolic concentrations and terminate Ca2+ signaling.
*
The Structure of Ca2+/Calmodulin
Figure 15-33. Molecular Biology of the Cell 6e (Garland Science, 2015).
Calmodulin is a Ca2+ binding protein whichbinds to and activates enzymes. Serves as a Ca2+ dependent regulatory subunit in many enzyme complexes. This family of enzymes is Ca2+/calmodulin-dependent kinases (CaM-kinases). They phosphorylate a variety of target proteins.
*
Some Cell Responses in Which GPCRs Activate PLC
Table 15-2. Molecular Biology of the Cell 6e (Garland Science, 2015).
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