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SignalTransduction

Pathways
By Haylee Sonnenberg

When signal receptors are plasma-membrane proteins, the


transduction stage of cell signaling is usually a multi-step
pathway.
Multi-step pathway benefits:
Signal amplification: large number of activated molecules at
the end.
More opportunities for coordination and regulation.

Pathways relay signals from receptors to


cellular responses
The binding of a specific extracellular signal molecule to a receptor
in the plasma membrane sparks step #1 in the molecular
interactions chainthe signal-transduction pathwaythat leads to a
particular response within the cell.
Its just like falling dominoes: the signal-activated receptor
activates another protein which activates another molecule, and so
on, until the last protein is activated.
Relay molecules: the molecules that relay a signal from receptor to
response [mostly proteins].
Interactions of proteins are HUGE in cell signaling and regulation.
Remember: the original signal molecules are NEVER physically
passed down the pathway; the information is passed down.
At each step the signal changes form [usually a conformational
protein change brought on by phosphorylation].

Protein phosphorylation, a common mode of regulation in


cells, is a major mechanism of signal transduction

Protein kinase: the general name for an enzyme that transfers

phosphate groups from ATP to a protein.


Most cytoplasmic protein kinases dont act on themselves, but
on other substrate proteins.
They also phosphorylate their substances on either of 2 amino
acids: serine or threonine.
Many relay molecules in signal-transduction pathways are
protein kinases, and often act upon each other.

A phosphorylation cascade

Protein phosphorylation, a common mode of regulation in


cells, is a major mechanism of signal transduction

Protein kinases are ber important:


1% of our genes are codes to make kinases.
1 cell alone has hundreds of different kinds, each with specificity for a
different substrate protein.
Together, they regulate a large proportion of the 1000s of proteins in
a cell.
Abnormal activity of a kinase = abnormal cell growth and cancer.
For a cell to normally respond to an extracellular signal, it must have
mechanisms for turning off the signal-transduction pathway when the initial
signal is no longer present.
Protein phosphatases: enzymes that remove phosphate groups from
proteins.
The activity of a protein regulated by phosphorylation depends on the
balance in the cell between active kinase and active phosphatase
molecules.
When the extracellular signal molecule isnt there, active phosphatase
molecules prevail, and the signaling pathway and cellular response turn off.

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Not all components of signal-transduction pathways are proteins.
A lot of signaling pathways also consist of small, non-protein,
water-soluble molecules or ions, called second messengers.
[The extracellular signal molecule that binds to the membrane
receptor is a pathways first messenger.]
Since second messengers are small and water-soluble, they can
easily disperse throughout the cell by diffusion.
Second messengers take part in pathways initiated by G-proteinlinked receptors and tyrosine-kinase receptors.
The 2 most popular second messengers are cyclic AMP and
calcium ions [Ca2+].
Most relay proteins are sensitive to the cytosolic concentration of
either one or the other of these second messengers.

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Cyclic AMP
The moment Earl Sutherland had established that epinephrine
somehow causes glycogen to break down without passing
through the plasma membrane, the search began for the second
messenger that transmits the signal from the plasma membrane
to the metabolic machinery in the cytoplasm.
He found that the binding of epinephrine to the plasma
membrane of a liver cell raises the cytoplasmic concentration of
cyclic adenosine monophosphate, abbreviated cyclic AMP or
cAMP.

Cyclic AMP

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Cyclic AMP
An enzyme built into the plasma membrane, adenylyl cyclase,
converts ATP to cAMP in response to an extracellular signal
[epinephrine in this case].
Adenylyl cyclase only becomes active after epinephrine binds to a
specific receptor protein.
So, the first messenger, the hormone, causes a membrane enzyme to
synthesize cAMP, which then sends the signal to the cytoplasm.
The cAMP doesnt last long without the hormone, because another
enzyme converts the cAMP into AMP, which is an inactive product.
Another surge of epinephrine is required to raise the cytosolic
concentration of cAMP again.
Other hormones and signal molecules besides epinephrine trigger
cAMP pathways, like G proteins, G-protein-linked receptors, and protein
kinases.

cAMP as a second
messenger

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Cyclic AMP
Protein kinase A, a serine/threonine kinase, is usually the relay molecule
immediately after cAMP in a signaling pathway. cAMP activates this kinase.
The active kinase then phosphorylates other proteins in the cell.
G-proteins inhibit adenylyl cyclase. For these systems, a different signal
molecule activates a different receptor, which then activates an inhibitory G
protein.
Certain microbes cause disease. Take cholera, for example. People acquire
Vibrio cholerae, the cholera bacteria, from bad drinking water. The bacteria
colonizes the small intestine lining and produces a toxin, which for cholera
is an enzyme that chemically changes a G protein involved in regulating
salt and water secretion. Since the modified G protein is now unable to
hydrolyze GTP to GDP, it stays forever stuck in its active form, continuously
causing adenylyl cyclase to make cAMP. The high concentration of cAMP
causes a high secretion of water and salts into the intestines. In the end,
the infected person develops horrible diarrhea and can die if untreated from
salt and water depletion.

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Calcium Ions and Inositol Trisphosphate
Many signal molecules in animals cause responses in their target
cells via signal-transduction pathways that increase the cytosolic
concentration of calcium ions.
Ca2+ are even more widely used than cAMP as a second messenger.
Raising the cytosolic Ca2+ concentration causes many responses in
animal cells [muscle cell contraction, secretion of certain
substances, and cell division].
In plant cells, Ca2+ act as a second messenger in signaling
pathways for coping with environmental stresses, like drought or
cold.
Cells use Ca2+ as a second messenger in G-protein pathways and
tyrosine-kinase receptor pathways.
Although cells always contain some Ca2+, this ion can function as a
second messenger because its concentration in the cytosol is
normally much lower than in the cell.

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Calcium Ions and Inositol Trisphosphate
Ca2+ are actively transported out of the cell and are actively
imported from the cytosol into the ER [sometimes even into
mitochondria and chloroplasts].
Because of this, the calcium concentration in the ER is usually
much higher than in the cytosol.

Calcium ion concentrations in an animal


cell

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Calcium Ions and Inositol Trisphosphate
Because the cytosolic calcium level is low, a small change in
the number of ions represents a relatively large percentage
change in calcium concentration.
In response to a signal relayed by a signal-transduction
pathway, the cytosolic calcium level may rise, usually by a
mechanism that releases Ca2+ from the cells ER.
The pathways leading to calcium release involve yet other
second messengers, diacylglycerol (DAG) and inositol
trisphosphate (IP3).
These 2 messengers are produced by a split of a certain kind of
phospholipid in the plasma membrane.

Calcium and inositol trisphosphate in


signaling pathways

Certain small molecules and ions are key


components of signaling pathways
[second messengers]
Calcium Ions and Inositol Trisphosphate
Because IP3 acts before calcium in the pathway, calcium could be
considered a third messenger.
However, the term second messenger is used for all small, nonprotein components of signal-transduction pathways.
Sometimes, Ca2+ activate a signal-transduction protein directly,
but often they function by means of calmodulin, a Ca2+-binding
protein present at high levels in eukaryotic cells.
Calmodulin mediates many calcium-regulated processes in cells.
When calcium ions bind to it, calmodulin changes conformation and
then binds to other proteins, activating or inactivating them.
The proteins most often regulated by calmodulin are protein
kinases and phosphatasesthe most common relay proteins in
signaling pathways.

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