Signal transduction pathways

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Signal transduction pathways Ligand binds to
specific receptor Pathways relay information
from plasma membrane to interior of
cell Changes are initiated along the way effect
on cell behavior and/or gene expression protei
n phosphorylation second messengers
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General description of pathways Interactions
with specific receptors Triggering events
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Ion channels Tyrosine kinase pathways G
protein-linked receptors Intracellular receptors
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Ion channels Salty taste Sour taste
(acids) Calcium channels Often provides
electrical stimulation of a neuron
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Pathways pass on information through binding
events binding?change in protein
conformation ? activation Phosphoryl
ation is often the triggering event Kinases
enzymes that catalyze this
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Tyrosine kinases phosphorylate themselves
Most kinases phosphorylate other proteins, on
serine or threonine (OH groups)
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Proteins are activated by kinase
activity Inactivated by protein
phosphatases Many different kinases, each with a
different substrate specificity If kinases are
defective in some way they may not be regulated
properly
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Example src A normal (cellular) form (c-src)and
an oncogenic form (v-src) of the genes are
known c-Src contains a tyrosine residue that,
when phosphorylated, INACTIVATES the
protein v-Src is missing this residue, so it is
stuck in the on position Cell growth is
uncontrolled, leads to cancer (oncogene)
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Protein kinase defects are associated
with several types of cancer Kinase inhibitors
may control growth of these cells Example
Gleevec? inhibits Bcr-Abl kinase (aberrant
kinase that causes a form of leukemia) Since
inhibitor is specific for that kinase, it can
target cancer cells with few side effects
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Second messengers small, water-soluble
molecules that diffuse rapidly through
cells cyclic AMP calcium are especially
common these can interact with many different
molecules
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Where is adenylyl cyclase?
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Note G protein
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cAMP is quickly inactivated by phospho- diesteras
e Primary target of cAMP is protein kinase
A (PKA) PKA has 4 subunits 2 regulatory, 2
catalytic cAMP binds to regulatory
subunits catalytic subunits now detach and
are activated
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Some effects of cAMP (cell-specific) In skeletal
muscle and liver?glycogenolysis Cardiac muscle-
strengthens muscle contraction Smooth muscle-
inhibits contraction Intestinal epithelium-
movement of salt and water into gut
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Why different effects? Some G proteins stimulate
signal transduction (Gs s stands for
stimulatory) Some inhibit signal transduction
(Gi) There are many different kinds of G
proteins some have 3 subunits, some only
one Distributed differently on different cells
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What sorts of binding events affect cAMP
levels? Epinephrine- glycogen metabolism break
down glycogen inhibit glycogen formation Seroto
nin- enhances synaptic transmission (via PKA
activation) Gene expression (PKA-activated
protein actually binds to DNA and promotes
transcription)
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Some compounds can affect this pathway without
ligand/G-protein interaction Caffeine inhibits
phosphodiesterase (to what effect?) Theophylline
- same effect smooth muscle relaxant
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Disruption of G protein signaling and disease A
tale of two toxins Cholera toxin modifies Gs so
that it cannot be inactivated Pertussis toxin
modifies Gi so it cannot inhibit adenylyl
cyclase Same effect, two different
mechanisms, different target cells
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One response to cAMP-mediated signaling
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Calcium ions and their associates Neurotransmitte
rs Growth factors Some hormones Increase in
cytoplasmic concentration of calcium contributes
to Muscle cell contraction Neurotransmitter
release Antibody production Insulin
secretion Among others
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Both G-protein and tyrosine kinase pathways can
utilize calcium as a second messenger Calcium
concentrations in cytoplasm are normally very
low Where does the calcium come from? from the
extracellular environment from the ER (calcium
is exported by calcium pumps within cell, to
keep internal calcium levels low)
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How is calcium released from internal
stores? Phospholipase C is activated (different
forms are activated by receptor tyrosine kinases
than by G protein-linked receptors) It cleaves
a membrane phospholipid (PIP2) to form
diacylglycerol (DAG) and inositol trisphosphate
(IP3)
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Both DAG and IP3 act as second messengers
in many types of cells Discovered in insect
salivary glands (early 1980s) Other
functions platelet activation muscle
contraction antibody secretion Among
others What do these second messengers do?
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DAG activates protein kinase C (PKC) phosphorylat
es many target proteins, at serines or
threonines PKC activation (you guessed it) does
many things in cells, including Cell
growth Activation of ion channels Protein
secretion Through its ability to phosphorylate
kinases associated with growth
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What about IP3?
Ca levels are now high enough to bind calmodulin
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Many cellular proteins have binding sites
for calcium-calmodulin complex Actual
identities of these proteins varies within
cells Tend to be kinases and phosphatases When
calcium levels drop, calmodulin releases calcium
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Outcomes of cell signaling Enzyme
activation Amplification Transcription and
translation of specific gene(s)
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Enzyme activation amplification
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(why is there gene expression in response to
this ligand?
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How can cells respond differently to
same stimulus Own set of receptors (with
characteristic tyrosine kinases, G proteins,
etc.) Own set of relay and functional proteins
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