Cell Signaling

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Cell Signaling

• Wednesday, July 23

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Cell Communication

• Essential for communication between cells in
  multicellular organisms
• Important for communication between unicellular
  organisms
• Cells detect, process, and respond to signals
• Chemical
• Physical
• Electromagnetic
• Mechanical

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Communication between yeast

• Mating signals
• Two sexes a and a
• a cells secrete a chemical a factor, which binds
  to receptors on a cells
• a cells secrete a chemical a factor, which binds
  to receptors on a cells
• Transduction of the signal causes a cellular
  repsonse
• Growth towards the opposite cell and fuse together

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Figure 11.2 Communication among bacteria

• Myxobacteria use chemical signaling to share
  information about nutrient supply
• Staving cells secrete a chemical signal
• Signal stimulates neighboring cells to aggregate
• Cells form a thick-walled spore structure capable
  of surviving until conditions improve

Individual rod shaped cells
Aggregation in progress
Spore-forming structure
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Figure 11.3 Local and long-distance cell
communication in animals
eg growth factors
Only specific target cells recognize and respond
to a given chemical signal
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Figure 11.4 Communication by direct contact
between cells
Molecules passes freely between adjacent cells
without crossing the plasma membrane
Cells communicate by interactions between
molecules on their surface
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Figure 11.5 Overview of cell signaling
Signal Reception detection of a signal coming
from outside the cell. A protein (signal) binds
a surface receptor (detection).
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Figure 11.5 Overview of cell signaling
Signal Transduction binding the signal molecule
causes a change in the receptor which initiates a
pathway that relays the response. The
cytoplasmic molecules that transmit the signal
are termed messengers.
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Figure 11.5 Overview of cell signaling
Signal Response the signal is transmitted to a
target molecule which causes triggers a specific
cellular response (chemical reaction, cell
movement, activation of specific genes, etc.).
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Signal Reception

• Chemical signals (ligands) - bind to a specific
  receptor
• The ligand is complementary in shape to a
  specific site on the receptor
• The signal receptor identifies the cell as the
  target
• Ligand binding causes a conformational change in
  the receptor and activates it
• Transmits signals from water-soluble proteins in
  the extracellular environment to the inside of
  the cell
• Signal receptors
• Plasma membrane proteins
• G-protein-linked receptors
• Tyrosine-kinase receptors
• Ion-channel receptors
• Intracellular Receptors

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Figure 11.6 The structure of a G-protein-linked
receptor
Seven a-helix spanning the membrane
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Figure 11.7 The functioning of a
G-protein-linked receptor

• G protein functions as a switch
• Off bound to ADP
• On bound to ATP
• Signal binds activating the receptor to bind a G
  protien and displace GDP for GTP
• GTP activates the G protein
• Activated G protein translocates along the
  membrane and binds the enzyme
• The enzyme is activated to trigger the signal
  transduction pathway
• G protein hydrolyzes GTP to GDP inactivating
  transduction

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Figure 11.8 The structure and function of a
tyrosine-kinase receptor
This receptor has enzymatic activity in its
cytoplasmic region that catalyzes the transfer of
a phosphate group to a tyrosine amino acid within
a protein. Receptor activation involves the
dimerization of two individually inactive
monomers which then phosphorylate and activate
each other. Activated receptor can then
phosphorylate many specific intracellular
proteins.
This single receptor can activate many pathways
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Figure 11.9 A ligand-gated ion-channel receptor

• Receptors are protein pores in the membrane that
  open or close in response to a chemical signal,
  regulating the flow of specific ions (Na, Ca).
• The opening of a channel immediately leads to a
  change in concentration of an ion in the cell
• This concentration change triggers further steps
  in a signal pathway

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Figure 11.10 Steroid hormone interacting with an
intracellular receptor
Intracellular Receptors

• Chemical signals cross the membrane to bind to
  their cytosolic receptor
• Hydrophobic signals steroid/thyroid hormones and
  NO gas
• Target cells contain the specific receptor which
  becomes activated upon ligand binding
• Activated receptor can then initiate the cellular
  response, such as turning on specific genes in
  the nucleus (transcription factors)

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Signal Transduction

• Relays signal from receptor to cellular response
  by way of protein interactions
• Multistep pathway signal cascade
• Amplification of signal
• Each molecule in the pathway can activate more
  than one downstream molecule
• A small number of extracellular signals produce a
  large cellular response
• Opportunities for coordination and regulation

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Mechanism of Signal Transduction

• Phosphorylation induced conformational change of
  protein messengers
• Protein kinases enzyme that transfers a
  phosphate group from ATP to amino acids on a
  substrate protein
• Tyrosine kinase
• Serine/Threonine kinase
• Protein Phosphatases enzyme that removes a
  phosphate group from proteins
• Signal regulation depends on the balance between
  active kinase molecules and active phosphatase
  molecules in the cell

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Figure 11.11 A phosphorylation cascade
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Figure 11.12 Cyclic AMP
Components of Signaling Pathways

• Proteins (G prtoteins, enzymes, transcription
  factors)
• Second messengers (small molecules and ions that
  can spread rapidly through the cell by diffusion)
• Cyclic AMP
• Calcium ions and inositol trisphosphate

Membrane enzyme activated by ligand binding
Inactivates cAMP
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Figure 11.13 cAMP as a second messenger
Phosphorylates other proteins depending on the
cell type
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Figure 11.14 The maintenance of calcium ion
concentrations in an animal cell
Secondary Messenger Ca

• Ca is maintained at a much lower concentration
  inside the cytosol
• Ca is actively pumped out of the cytosol and
  into the extracellular fluid or into the ER
• A signal may cause cytosolic Ca to rise by its
  release from the ER

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Figure 11.15 Pathway Leading to Calcium Release
PLC may be activated by G protein receptor or
Tyrosine kinase pathways
Activated PLC cleaves PIP2 into DAG
(diacylglycerol) and IP3 (inositol trisphosphate)
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Figure 11.15 Pathway Leading to Calcium Release
IP3 acts as a second messenger that diffuses
through the cytosol and binds a ligand-gated Ca
channel in the ER membrane, causing it to open.
Ca ions flow out of the ER into the cytosol and
activate the next protein in the pathway (usually
Calmodulin, a Ca binding protein)
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Figure 11.15 Pathway Leading to Calcium Release
Calmodulin-Ca can then activate one or more
signaling pathways resulting in a cellular
response
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Cellular Response

• Regulate activities in the cytoplasm (eg
  response to epinephrine)
• Activate enzymatic activity
• Open or close an ion channel
• Regulate transcription in the nucleus (eg
  response to a growth factor)
• Activate transcription of a gene
• Synthesis of enzymes or other proteins
• Inhibit transcription of a gene

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Cytoplasmic response to a signal stimulation of
glycogen breakdown by epinephrine
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Cellular Response

• Regulate activities in the cytoplasm (eg
  response to epinephrine)
• Activate enzymatic activity
• Open or close an ion channel
• Regulate transcription in the nucleus (eg
  response to a growth factor)
• Activate transcription of a gene
• Synthesis of enzymes or other proteins
• Inhibit transcription of a gene

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Fig. 11.17 Nuclear response to a signal
activation of a specific gene by a growth factor
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Signaling Pathways

• Multistep pathway signal cascade
• Amplification of signal
• Each molecule in the pathway can activate more
  than one downstream molecule
• Proteins persist in an active form long enough to
  process numerous molecules of substrate before
  they become inactive again
• Specificity of signal
• Cells respond to some signals and ignore others
• Different cells produce different responses to
  the same signal
• Response of a particular cell to a signal depends
  on its unique collection of signal receptors,
  messengers, and response proteins

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Figure 11.18 The specificity of cell signaling
Four cells respond differently to the same
signal Different sets of proteins possessed by
each cell determines what signal molecules it
responds to and the nature of the response.
Different pathways may have some molecules in
common.
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Efficiency of Signaling

• How do signaling molecules in the cytoplasm find
  their substrate?
• Scaffolding proteins large relay proteins to
  which several other relay proteins are
  simultaneously attached
• Facilitates a specific signal cascade
• Enhances speed and efficiency of signal
• May permanently hold together networks of
  signaling-pathway proteins

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Figure 11.19 A scaffolding protein
Scaffolding proteins binds a membrane receptor
and 3 different protein kinases
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Regulating Signals

• Cells must inactivate a signal response
• Each participating molecules must be short-lived
  in order to enable the cell to respond quickly to
  many incoming signals
• The changes that a signal produces are reversible
• When the signal is removed, receptor revert to an
  inactive form
• Relay molecules return to their inactive forms