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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 outside
(sensor)
inside (cytosol)

Transduction
Cascade

Something
Output
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
• 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: Now:
Enumerate • Modules
components • Circuits/
Design Logic
• Cross-talk
• Specificity
Adrenaline
signaling
• Signal: Adrenaline (epinephrine)
– Secreted by adrenal gland

• Receptor: β -adrenergic receptor

• Response:
– Breakdown of glycogen to glucose to
provide energy for “fight-or-flight”
Insulin
signaling
• Signal: insulin
– Secreted by β 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

NUTRIENTS
unicellular
eukaryote

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

• 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
PP P
ATP

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 P
MEK MEK
P P
TXY TXY
MAPK MAPK
P P
SP TP SP TP
g r o w th fa c to r
HER2
re c e p to r
Ras

MEKK Raf

M E K /M A P K K
MEK1 MEK2

MAPKs
E R K 1E R K 2

E lk 1 /S R F F o s J u n c y c lin D 1

F O S

N e o p la s tic p h e n o ty p e
C C N D 1
Specificity in MAPK Signalling

How do protein
kinases recognize
their protein
substrates ?
Protein Kinase Reaction

Kinase
PP P
ATP

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.
Bardwell Lab
• Lee Bardwell
• Jane Bardwell
• Kandarp Shah
• Lamar Blackwell
• Tom Whisenant
• Jeff Rogers
• Pascal Krotee