Signal Transduction

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Signal Transduction Signal Transduction is the
process by which a cell converts an
extracellular signal into a response. Involved
in Cell-cell communication Cells response to
environment Intracellular homeostatsis- internal
communication
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Generic Signaling Pathway
Signal Receptor Transduction Cascade Targets
Response
Metabolic Enzyme
Cytoskeletal Protein
Gene Regulator
Altered Metabolism
Altered Gene Expression
Altered Cell Shape or Motility
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
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Components of Signaling
External signal what is it?

• Peptides / Proteins- Growth Factors
• Amino acid derivatives - epinephrine, histamine
• Other small biomolecules - ATP
• Steroids, prostaglandins
• Gases - Nitric Oxide (NO)
• Photons
• Damaged DNA
• Odorants

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Components of Signaling
How is the signal received?
Ligand/receptor- A molecule that binds to a
specific site on another molecule, usually a
protein
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Generic Signaling Pathway
Signal Receptor (sensor) Transduction
Cascade Targets Response
Metabolic Enzyme
Cytoskeletal Protein
Gene Regulator
Altered Metabolism
Altered Gene Expression
Altered Cell Shape or Motility
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
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Components of Signalling
Hydrophillic Ligand
Cell-Surface Receptor
Cell surface Intracellular
Plasma membrane
Hydrophobic Ligand
Carrier Protein
Intracellular Receptor
Nucleus
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
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• Cell Surface Receptor Types
• 1) Lipid-soluble ligand

Hydrophobic Ligand
Intracellular Receptor
Nucleus
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• Cell Surface Receptor Types
• 2) Ligand gated channel

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• Cell Surface Receptor Types
• 3) G-Protein Coupled Receptor

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• Cell Surface Receptor Types
• 4) Enzyme-linked Receptor
• eg Growth Factor Receptors

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Most growth factors bind Receptor Tyrosine Kinases
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Growth Factor Receptor Activation I
RTK
RS/TK
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Growth Factor Receptor Activation II
Ligand binding induces receptor
dimerization Activation of kinase and
autophosphorylation Initiation of intracellular
cascades
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Signaling in the Nervous System Domains,
Domains
1. Protein Domains
2. Neuronal Survival Neurotrophic Hypothesis
- Trks
3. Axon Guidance EphA4/ephrin DCC/Netrin
4. Synapse Formation and Function PSD-95
scaffolds rac/rho/cdc42
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Generic Signaling Pathway
Signal Receptor (sensor) Transduction
Cascade Targets Response
Metabolic Enzyme
Cytoskeletal Protein
Gene Regulator
Altered Metabolism
Altered Gene Expression
Altered Cell Shape or Motility
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
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Signal Transduction Downstream effectors
Protein Signaling Modules (Domains)
SH2 and PTB bind to tyrosine phosphorylated
sites SH3 and WW bind to proline-rich
sequences PDZ domains bind to hydrophobic
residues at the C-termini of target proteins PH
domains bind to different phosphoinositides FYVE
domains specifically bind to Pdtlns(3)P
(phosphatidylinositol 3-phosphate)
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Examples of Protein Domains
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
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Examples of Protein Domains and folds
EVH1
PDZ domain
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Domains are linked to give specificity of
function to a protein
SH3 domain
Proline rich regions
SH2 domain
pY motif
SH3 and SH2 domains of Src
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
Many domains are not unique to one protein.
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Domains are linked to give specificity of
function to a protein or protein family. Domains
are not unique to one protein
PDZ
PDZ
PDZ
Par3
PDZ
Par6
crib
kinase
aPKC
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
Many domains are not unique to one protein.
Domains allow for signaling diversity and
function.
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
Many domains are not unique to one protein.
Domains allow for signaling diversity and
function.
Most domains recognize short linear sequences
from 4 to 10 amino acids in length. Some domains
recognize specific phospholipids.
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Domains bind short stretches of amino acids. The
amino and carboxyl terminal amino acids give rise
to specificity and diversity
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Examples of signal integration properties of
domains
Seet et al. Nature Reviews Molecular Cell Biology
7, 473483
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
Many domains are not unique to one protein.
Domains allow for signaling diversity and
function.
Most domains recognize short linear sequences
from 4 to 10 amino acids in length. Some domains
recognize specific phospholipids.
Understanding domain function and structure is
important for drug development.
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Kinases have two lobes
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Chronic myelogenous leukemia (CML1)
Chimeric BCR-ABL gene had protein-tyrosine kinase
(PTK) activity that was deregulated compared with
normal Abl and correlated with its ability to
transform cells to a malignant phenotype
The incidence of CML is approximately 1 to 1.5/105
The catalytic domains of eukaryotic kinases have
a highly conserved bilobed structure. The
(N-lobe) contains a beta-sheet and a conserved
helix. The C-lobe is helical. In the interface
between the two lobes, a series of highly
conserved residues form the ATP binding and
catalytic sites.
The activation state of kinases is dependent on
the position of the activation loop (A-loop). In
inactive kinases the A-loop is pointed in. In the
activated state the loop is out and allows
binding of the substrate
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Knowledge of protein domains and their structure
allows us to develop drugs that will function to
inhibit a protein domain and thus protein function
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Protein Domains
Within a protein - a domain is a structural
element.
Domains have folds within them giving rise to
their specificity.
Domains often fold independently of the rest of
the protein.
N and C terminal regions are often found on same
face allowing for multiple domains within the
same protein.
Many domains are not unique to one protein.
Domains allow for signaling diversity and
function.
Most domains recognize short linear sequences
from 4 to 10 amino acids in length. Some domains
recognize specific phospholipids.
Understanding domain function and structure is
important for drug development.
35
Signaling in the Nervous System Domains,
Domains
1. Protein Domains
2. Neuronal Survival Neurotrophic Hypothesis
- Trks
3. Axon Guidance EphA4/ephrin DCC/Netrin
4. Synapse Formation and Function PSD-95
scaffolds rac/rho/cdc42