Alberts • Bray • Hopkin • Johnson • Lewis • Raff • Roberts • Walter
Essential
Cell Biology
FOURTH EDITION
Chapter 16
Cell Signaling
Copyright © Garland Science 2014
Like your cell phone, cells receive signals from
the outside that bring about a behavioral response.
Fig. 16-2
Signals can act over long or short range.
Fig. 16-3
Long Range Acting
fight or flight response
Short Range Acting
shortest
The same signal can
induce different responses
in different cells.
non-ion
channel
receptor
sarcomere-like
Fig. 16-5
secretory vesicles
ion channel
receptor
sarcomere
Response depends on end target proteins present in each cell,
as well as which cell surface receptor is involved.
Cells integrate multiple signals to
induce a specific response.
Fig. 16-6
Responses can be fast or slow, depending on
whether transcription and translation are required.
Fig. 16-7
Signals are received by receptors, which can
act on the cell surface or intracellularly.
not membranepermeable
membrane-permeable
Fig. 16-7
Steroid hormones are
hydrophobic enough
to cross a plasma
membrane and bind
cytosolic nuclear
receptors.
Fig. 16-10
Steroid hormones are derived from cholesterol.
Fig. 16-9
polar modifications needed
to make more soluble
for function as endocrines
Blood vessel dilation involves
both membrane permeable and
non-permeable signals.
-Acetylcholine (non-permeable signal)
induces production of diffusible signal
(NO gas) from endothelial cells
-NO gas (permeable signal) induces
production of cGMP second messenger
in smooth muscle cells
Nitric
Acetylcholine:
not membrane-soluble
Oxide NO:
membrane-soluble
Fig. 16-11
Cell-surface receptors relay the signal through
intracellular signaling molecules to final targets.
signal transduced
through chain reaction
of signal molecules
leading to final response
Fig. 16-12
Examples: kinases and G proteins
Common intracellular signaling proteins
Fig. 16-15
It must be possible for these to return to
ground state, so they can receive future signals.
Phosphatases return protein kinases
and their targets to ground state.
sometimes
dephosphorylation
turns protein ON
Fig. 16-15a
GTP hydrolysis returns G proteins to ground state.
Fig.16-15b
16-15a
Fig.
Monomeric G proteins are
assisted by GEFs and GAPs
Guanine nucleotide
Exchange Factor
activates
inactivates
GTPase-Activating
Protein
Fig. 16-16
Three Classes of
Membrane-Bound
Receptors
Fig. 16-17
Ion-Channel-Coupled Receptors
Responsible for depolarizing
post-synaptic membranes to threshold
fast and short range
Fig. 16-17a
Example: Acetylcholine Receptor in skeletal muscle
GPCR
G Protein-Coupled Receptor
Can Achieve Astonishing Speed and Sensitivity
largest family of cell surface receptor; > 800 types in humans
Fig. 16-17b
Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.
Fig. 16-17c
GPCR
-contain seven
transmembrane α-helix
domains
-signal binding induces
conformational change
by shifting positions of
transmembrane domains
-activates G protein
Signaling molecule
depicted here: Adrenaline
Fig. 16-18
Conformational change activates G protein complex
active G protein
switches effector
to “on” state
Fig. 16-19
G protein switches itself off through GTP hydrolysis
What would
happen if
GTP-hydrolysis
activity mutated?
Fig. 16-20
Locked in
Active State
Activated G protein complex directly stimulates
K+ channel opening in heart pacemaker cells
βγ
Fig. 16-21
K+ flow out
hyperpolarizes
cell membrane,
making harder
to activate
But many Gα subunits activate enzymes
to produce 2nd messenger molecules
Fig. 16-22
cAMP is a common
second messenger
synthesized from ATP by
adenylyl cyclase enzyme
destroyed by hydrolysis
to AMP by cyclic AMP
phosphodiesterase enzyme
Fig. 16-23
GPCR couples to G protein complex
G protein complexes activate cAMP
production by Adenylyl Cyclase
GPCR with adrenaline signal
in “fight or flight” response
Table 16-3
Adrenaline: synthesized from Tyrosine
GPCR and cAMP in Glycogen Breakdown
Gαs
Gαs:stimulates adenelyl cyclase
Gαi: inhibits adenylyl cyclase
also stimulated
By Glucagon
during starvation
Fig. 16-25
PKA target:
phosphorylase kinase
Cystic Fibrosis transporter (CFTR) and cAMP
regulate H2O efflux into respiratory & intestinal passages
Gαs
GPCR
Cholera toxin locks Gα in active state
CFTR +/- : beneficial
CFTR -/- : Cystic Fibrosis
H 2O
H 2O
cAMP stimulates CFTR phosphorylation by PKA
Rhodopsin is a light-activated GPCR
with cGMP second messenger
Gαt
light activates
cGMP destruction
Fig. 16-30 & 31
inhibiting neurotransmission
GPCR coupled to Gαq activates
phospholipase instead of adenylyl cyclase
DAG
stimulates smooth
muscle contraction
Fig. 16-27
lipid cleavage products and Ca2+ act as second messengers
Enzyme-Coupled Receptors
Responses typically slow, but highly sensitive.
Fig. 16-17c
Many Enzyme-Coupled Receptors are
Receptor Tyrosine Kinases (RTKs)
auto-phosphorylation
Fig. 16-32
through phosphorylation
Most RTKs activate the
monomeric G protein, Ras
Fig. 16-33
Ras GOF mutations
in 30% human cancers!
cellular response
often cell growth
& proliferation
Activated Ras initiates phosphorylation cascade
amplifies signal
Fig. 16-34
Cyclin genes, etc.
Survival and growth signals
induce membrane localization of kinases
lipid phosphorylation
Insulin is survival/growth signal
Fig. 16-35
membrane localization of
PH domain kinases (Lab 4B)
Activated Akt inactivates pro-apoptotic Bad
and activates anti-apoptotic Bcl2
Fig. 16-36
Activated Akt
also stimulates growth
through
nutrient/energysensing Tor kinase
Fig. 16-39
Insulin also stimulates GLUT4 membrane
recruitment for glucose uptake.
Akt
Animation
Karp CMB7
WELL FED
GLUCOSE
insulin
LAB 4B
PH-GFP (tGPH)
PO4
Akt InR GLUT4
PI3K
Acetylation of
TXN factors for
starvation genes
Low
NAD+
no glucose
STARVATION
Deacetylation
of TXN factors
by Sirtuins
TXN-ac
factors
inactive
Sirtuins
Active Insulin Signaling
PH-domain proteins:
membrane-localized
TXN
factors
High
NAD+
Active
Sirtuins
No Insulin Signaling
PH-domain proteins:
cytosolic and nuclear
Receptor Mutations
Loss vs. Gain
of Function
Loss of Function: reduced response to signal
Y2 changed
to glutamic acid
wild type receptor
Gain of Function: response in absence of signal
Cells integrate multiple signals
into complex responses.
Fig. 16-43
Plants and animals evolved
signaling systems independently.
Plants use very different
processes.
Plants do not use RTKs,
steroid hormone nuclear
receptors, or cAMP, and
few GPCRs.
They do use cell surface
Receptor Ser/Thr Kinases
(Ethylene Receptor).
Empty receptor activates kinase,
but inactivates gene expression.
Fig. 16-42