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Cell Signaling
2007
Cell Signaling
• Cells sense and send information (signals)
• Cells communicate with each other
• Cells must sense and respond to changes in
the environment
The signal can come from inside the cell,
from another cell, or from the environment.
©2004 Lee Bardwell
Generic Signaling Pathway
Signal
Receptor
(sensor)
outside
inside (cytosol)
Transduction
Cascade
Output
Something
happens
©2002 Lee Bardwell
Responses to cell signaling
Something
happens
biochemically
• Gene expression is altered at the level of
transcription, RNA processing or translation
• Enzyme activities are altered
• Protein-protein interactions are induced or
inhibited
• The localization of certain proteins and other
stuff is altered
©2002 Lee Bardwell
Responses to cell signaling
Something
happens
Physiologically
The Cell…
– divides or stops dividing
– differentiates
– commits suicide or kills something
– moves somewhere or stops moving
– alters its metabolism
– passes on the signal
©2002 Lee Bardwell
What can be a signal?
- almost anything
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Peptides - insulin, glucagon...
Proteins
Amino acid derivatives - epinephrine, histamine
Other small biomolecules - ATP
Steroids, prostaglandins
Gases - Nitric Oxide (NO)
Photons
Damaged DNA
Odorants, tastants
©2002 Lee Bardwell
Steroid Hormone Signaling Pathway
Signal
(steroid)
Receptor
(txn factor)
Steroid Hormone Signaling Pathway
Output
∆ gene expression
∆ cell physiology
Signaling cascades have many steps
Past:
Enumerate
components
Now:
• Modules
• Circuits/
Design Logic
• Cross-talk
• Specificity
Adrenaline
signaling
• Signal: Adrenaline (epinephrine)
– Secreted by adrenal gland
• Receptor: b-adrenergic receptor
• Response:
– Breakdown of glycogen to glucose to
provide energy for “fight-or-flight”
Insulin
signaling
• Signal: insulin
– Secreted by b cells of pancreas
• Receptor: a receptor kinase
• Response:
– Sugar is taken up from bloodstream into
cells
• Diabetes - type 1, type 2
Growth factor signaling
The growth of multicellular organisms is
regulated by more than just nutrient availability
unicellular
eukaryote
NUTRIENTS
NUTRIENTS
multicellular
eukaryote
a edigner
Cells in multicellular eukaryotes require
permission signals from growth factors
NUTRIENTS
NUTRIENTS
a edigner
Disregulation of growth factor signal
transduction leads to cancer
NUTRIENTS
NUTRIENTS
cellular
transformation
Some growth factors
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EGF - epidermal growth factor
FGF - fibroblast growth factor
NGF - nerve growth factor
PDGF - platelet-derived growth factor
Insulin-like GF
All of these bind to a class of receptors known as
“Receptor Kinases”
Receptors with enzymatic
activity
Protein kinases and
phosphatases
- Add/remove phosphates to/from proteins
- Involved in all signaling from cell surface
recetors, and in most other signaling too
©2002 Lee Bardwell
Protein Kinase Reaction
Kinase
ATP
PP
P
Substrate
Protein Kinase Reaction
Phosphorylation of protein substrates
PP
P
Product
Phosphorylation can flip a protein from
“active” to “inactive” or vis-versa
ATP
ADP
The Mitogen-Activated Protein Kinase
(MAPK) Cascade
RAF
P
MEK
P
MEK
P
TXY
MAPK
P
TXY
MAPK
P
SP TP
P
SP TP
Specificity in MAPK Signalling
How do protein
kinases recognize
their protein
substrates ?
Protein Kinase Reaction
Kinase
ATP
PP
P
Substrate
Protein Kinase Reaction
Phosphorylation of protein substrates
PP
P
Product
Active site - target peptide interaction
is not enough for specificity
Kinase
Substrate
Tethering function: Grewal et al (2006) Cell. Signal. 18:123
Bardwell Lab
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Lee Bardwell
Jane Bardwell
Kandarp Shah
Lamar Blackwell
Tom Whisenant
Jeff Rogers
Pascal Krotee