Transcript Essential Cell Biology

Essential
Cell Biology
Third Edition
Chapter 16 Lecture Outlines
Cell Communication
Copyright © Garland Science 2010
CHAPTER CONTENTS
GENERAL PRINCIPLES OF CELL
SIGNALING
G-PROTEIN–COUPLED RECEPTORS
ENZYME-COUPLED RECEPTORS
Budding yeast cells are normal spherical (A) but when exposed to
mating factor produced by neighboring yeast cells they extend a
protrusion toward the source of the factor
Figure 16-1 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Signal transduction is the process whereby one type of signal
is converted to another.
(B) a target cell converts an extracellular signal (molecule A) into
an intracellular signal (molecule B)
Figure 16-2 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Signal can act over long or short range. There are
four types of cell communication: (A) endocrine: to long distance,
(B) papacrine: to nearby neighbor
Figure 16-3 Essential Cell Biology (© Garland Science 2010)
(C) Neuronal signaling,
(D) contact-dependent: don’t need secreted molecule
Contact-dependent signaling controls nerve-cell production:
Each future neuron delivers an inhibitory signal to the cells
next to it to deter them from specializing as neurons too
Figure 16-4 Essential Cell Biology (© Garland Science 2010)
Table 16-1 (part 1 of 2) Essential Cell Biology (© Garland Science 2010)
Table 16-1 (part 2 of 2) Essential Cell Biology (© Garland Science 2010)
Home work:
List all the signal molecule, its site of origin, its destination
and function.
Quiz will be given next week.
You are expected to know how to spell these signal molecules.
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Each cell responds to a limited set of signals:
The same signal molecule can induce different responses in different
target cells. e.g. acetylcholine
Figure 16-5 Essential Cell Biology (© Garland Science 2010)
Figure 16-5a Essential Cell Biology (© Garland Science 2010)
Figure 16-5b Essential Cell Biology (© Garland Science 2010)
Figure 16-5c Essential Cell Biology (© Garland Science 2010)
Figure 16-5d Essential Cell Biology (© Garland Science 2010)
An animal cell depends on multiple extracellular signals:
Figure 16-6 Essential Cell Biology (© Garland Science 2010)
1. Every cell type displays a set of receptor proteins that enables it to
respond to a specific set of signal molecules produced by other cells
2. Most cells undergo a form of cell suicide, programmed cell death,
or apoptosis if there is no signal
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Extracellular signals can act slowly or rapidly
Figure 16-7 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Extracellular signal molecules bind either to cell-surface receptors or
to intracellular enzymes or receptors
Figure 16-8 Essential Cell Biology (© Garland Science 2010)
Some extracellular signal molecule is large and hydrophilic, it
needs receptor on cell surface to deliver signal to cell
Figure 16-8a Essential Cell Biology (© Garland Science 2010)
Some small, hydrophobic extracellular signal can diffuse
across the membrane and binds to intracellular receptor
in either the cytosol or the nucleus
Figure 16-8b Essential Cell Biology (© Garland Science 2010)
Some small hydrophobic hormones binds to intracellular
receptors that act as transcription regulators
Figure 16-9 Essential Cell Biology (© Garland Science 2010)
The steroid hormone cortical acts by activating a transcription
regulator. Cortisol is one of the hormones produced by the adrenal
glands in response to stress
Figure 16-10 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Nitric oxide (NO) triggers smooth muscle relaxation in a blood-vessel
wall:
Figure 16-11a Essential Cell Biology (© Garland Science 2010)
1. Acetylcholine released by nerve terminal in the blood-vessel wall
stimulates endothelial cells lining the blood vessel to make and
release NO
2. NO diffuse from endothelial cell to adjacent smooth muscle cells
causing muscle cell relaxation
Figure 16-11b Essential Cell Biology (© Garland Science 2010)
One target protein that can be activated by NO is guanyl cyclase.
The activated cyclase catalyzes the production of cGTP from GTP
Figure 16-11c Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Many extracellular signals act via cell-surface receptors to change
the behavior of the cell. The receptor protein activates one or more
intracellular signaling pathways, each mediate by a series of
intracellular signaling molecules
Figure 16-12 Essential Cell Biology (© Garland Science 2010)
Intracellular signaling protein can relay, amplify, integrate and
distribute the incoming signal
Figure 16-13 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Many intracellular signaling proteins act as molecular switches
(A)Signaling by phosphorylation : signaling proteins are activated
by the addition of a phosphate group by protein kinase, and inactivated
by removal of the phosphate by protein phosphatase. Protein kinase
phosphates serine/threonine (called ser/thr kinase) or tyrosine (called
tyrosine kinase)
Figure 16-14 Essential Cell Biology (© Garland Science 2010)
(B) Signaling by GTP-binding protein: a GTP-binding signaling
protein is induced to exchange its bound GDT for GTP (i.e. adds a
phosphate to the protein). The hydrolysis of the bound GTP to GDP
Then switches the protein off
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Cell surface receptors fall into three basic classes:
1. An ion-channel-coupled opens or closes in response to binding of
its extracellular signal molecule. These channels are also called
‘transmitter-gated ion channels
Figure 16-15a Essential Cell Biology (© Garland Science 2010)
2. G-protein-coupled receptor: When a G-linked receptor binds its
extracellular signal molecule, the signal is passed first to a
GTP-binding protein (G protein) that is associated with the receptor.
The activated G protein then leaves the receptor and turn on a target
enzyme (or ion channel) in the membrane
Figure 16-15b Essential Cell Biology (© Garland Science 2010)
3. Enzyme-coupled receptors: An enzyme-linked receptor binds
its extracellular signal molecule, switching on an enzyme activity,
either at the other end of the enzyme or other associated enzyme
Figure 16-15c Essential Cell Biology (© Garland Science 2010)
EGF signaling pathway
Table 16-2 Essential Cell Biology (© Garland Science 2010)
GENERAL PRINCIPLES OF
CELL SIGNALING
• Signals Can Act over a Long or Short Range
• Each Cell Responds to a Limited Set of Signals,
Depending on Its History and Its Current State
• A Cell’s Response to a Signal Can Be Fast or Slow
• Some Hormones Cross the Plasma Membrane and
Bind to Intracellular Receptors
• Some Dissolved Gases Cross the Plasma Membrane
and Activate Intracellular Enzymes Directly
• Cell-Surface Receptors Relay Extracellular Signals
via Intracellular Signaling Pathways
• Some Intracellular Signaling Proteins Act as
Molecular Switches
• Cell-Surface Receptors Fall into Three Main Classes
• Ion-channel–coupled Receptors Convert Chemical
Signals into Electrical Ones
Ion-channel-coupled receptors convert chemical signals into
electrical ones:
Fig 12.24 the neuron-muscle junction. When the neurotransmitter
binds , this type of receptor alters its conformation so as to open
an ion channel in the plasma membrane
Movie 16.1
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
G-protein-coupled receptors:
Bind to signal molecule (ligand)
Binding to G protein inside the cell
Figure 16-16 Essential Cell Biology (© Garland Science 2010)
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
Figure 16-17 Essential Cell Biology (© Garland Science 2010)
Inactivated state
Figure 16-17a Essential Cell Biology (© Garland Science 2010)
Binding of signal molecule to
receptor causes the
conformation change of this
receptor, which in turn alters
the conformation of the
G protein
The alteration of the α subunit
of G protein allows it to
exchange its GDP to GTP.
This causes the G protein to
break up into two activate
components- α subunit and a
βγ complex, both can regulate
the activity of target proteins in
the plasma membrane
Figure 16-17b Essential Cell Biology (© Garland Science 2010)
The G-protein a subunit
switches itself off by
hydrolyzing its bound GTP
Figure 16-18 Essential Cell Biology (© Garland Science 2010)
Movie 16.2
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
G-protein-linked signaling :
Some G-protein regulate ion channels: e.g. G protein couple receptor
activation to opening of K+
channels in the plasma
membrane of heart
muscle cells
activated bg complex binds to
and opens a K+ channel
inactivation of the a subunit by
hydrolysis of its bound GTP
returns the G protein to its
inactive state, allowing the K+ channel to close
Figure 16-19 Essential Cell Biology (© Garland Science 2010)
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
1. Some G proteins activate membrane-bound enzymes: enzyme
activated by G proteins catalyze the synthesis of intracellular
second-messenger molecules
Figure 16-20 Essential Cell Biology (© Garland Science 2010)
cAMP as a second messenger
http://www.youtube.com/watch?v=MF0EjhcpAos
Second messenger: small molecule formed in or released into
the cytosol in response to an extracellular signal (first messenger)
that helps to relay the signal to the interior of the cell.
Examples include cAMP, IP3 and Ca 2+
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
c-AMP pathway: c-AMP is synthesized
by adenylyl cyclase and degraded by
c-AMP phosphodiesterase
Figure 16-21 Essential Cell Biology (© Garland Science 2010)
Example of c-AMP pathway: c-AMP (second messenger)
concentration rises rapidly in response to an extracellular signal
(first messenger)
A nerve cell in culture responds to the binding of the neurotransmitter serotonin
to a G-protein-linked receptor by synthesizing c-AMP
Figure 16-22 Essential Cell Biology (© Garland Science 2010)
Table 16-3 Essential Cell Biology (© Garland Science 2010)
c-AMP pathway: cyclic-AMP-dependent protein kinase (PKA)
1.c-AMP exerts various effects mainly by activating the
enzyme PKA
2.The binding of c-AMP causes the conformation change and
activate PKA. The activated PKA then phosphorates certain
intracellular proteins on its serine or threonine sites, thus altering
their activity
Example of cell using c-AMP pathway:
Adrenaline stimulates glycogen
breakdown in skeletal muscle cells
Figure 16-23 Essential Cell Biology (© Garland Science 2010)
A rise in intracellular cyclic AMP can activate gene transcription
Figure 16-24 Essential Cell Biology (© Garland Science 2010)
Movie 16.3
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
G-protein-linked signaling :
Inositol phospholipid pathway (PIP2):
Signal molecule binds to G-protein-linked receptor
PIP2 (phosphoinositol diphosphate)
phospholipase C
IP3 + DAG
DAG activates protein kinase C ,
IP3 open calcium channels from ER
Phospholipase C activates two signaling pathways
Figure 16-25 Essential Cell Biology (© Garland Science 2010)
Table 16-4 Essential Cell Biology (© Garland Science 2010)
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
G-protein-linked signaling :
Inositol phospholipid pathway:
1. A Ca 2+ signal triggers many biological process
Example: the fertilization of an egg by a sperm triggers an increase
cytosolic Ca 2+ in the egg
Figure 16-26 Essential Cell Biology (© Garland Science 2010)
2. The effect of Ca 2+ in the cytosol are largely indirect, they are
mediated through the interaction of Ca 2+ + with various transducer
protein, known collectively as Ca 2+ binding proteins, such as
calmodulin.
3. Once Ca 2+ binds with calmodulin, it forms Ca 2+ /calmodulindependent protein kinase (CaM-kinases), and they influence other
processes in the cell by phosphorylating selected proteins
Movie 16.4
Structure of Ca 2+ /calmodulin: (A) Calmodulin molecule has a
dumbbell shape with two globular ends connected by a long, flexible
a helix, each end has two Ca 2+ binding domains, (B) The conformational changes in Ca 2+ /calmodulin that occur when it binds to a
target protein
Figure 16-27 Essential Cell Biology (© Garland Science 2010)
Movie 16.5
G-PROTEIN–COUPLED RECEPTORS
• Stimulation of GPCRs Activates G-Protein
Subunits
• Some G Proteins Directly Regulate Ion
Channels
• Some G Proteins Activate Membrane-bound
Enzymes
• The Cyclic AMP Pathway Can Activate
Enzymes and Turn On Genes
• The Inositol Phospholipid Pathway Triggers a
Rise in Intracellular Ca2+
• A Ca2+ Signal Triggers Many Biological
Processes
• Intracellular Signaling Cascades Can Achieve
Astonishing Speed, Sensitivity, and
Adaptability
Intracellular signaling cascades can achieve astonishing speed,
sensitivity, and adaptability:
e.g. photoreceptor in the eye:
When the rod cell is stimulated by light,
a signal is relayed from the rhodopsin
molecule in the discs, through the crystal
of the outer segment, to Na+ channels in
the plasma membrane of the outer
segment.
The Na+ channels close in response to the
signal, producing a change in the membrane
potential of rod cell (hyper-polarization).
The change of membrane potential alters
the rate of neurotransmitter release from
the synaptic region of the cell
Figure 16-28 Essential Cell Biology (© Garland Science 2010)
Light reception by eye and signal transduction to SCN
(suprachiasmatic nuclei). Rods and cones, photoreceptor cells
located in the inner retina, mediate the perception of light.
the light-induced signaling
cascade in rod photoreceptor
cells greatly amplifies the
light signal
Figure 16-29 Essential Cell Biology (© Garland Science 2010)
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
Enzyme-coupled receptors
1. Enzyme-coupled receptors are transmembrane proteins that
display their ligand-binding domain on the outer surface of
the plasma membrane
2. The cytoplasmic domain of the receptor either acts as an
enzyme itself or forms a complex with another protein that
acts as an enzyme
3. Receptor tyrosine kinases (RTKs) is the largest class of
enzyme-coupled receptors in made up those with a cytoplasmic
domain that functions as a tyrosine protein kinase,
phosphorylating specific tyrosine on selected intracellular proteins
Activated receptor tyrosine kinase assemble a complex of
intracellular signaling proteins
Figure 16-30 Essential Cell Biology (© Garland Science 2010)
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
RTKs activate Ras
1.Ras: a small protein that is bound by a lipid tail to the cytoplasmic
face of the plasma membrane. The binding of Ras-activating protein
makes Ras exchange its bound GDP to GTP. The activated Ras then
stimulates the next steps in the signling pathway
Figure 16-31 Essential Cell Biology (© Garland Science 2010)
2. Adaptor: protein for helping to build a large signaling aggregate
by coupling the receptor to other proteins. Here the adaptor recruits
and stimulates Ras-activating protein
Ras activates a MAP-kinase Phosphorylation cascade
1.MAP kinase: protein kinase that performs a crucial step in
relaying signals from cell-surface receptors to the nucleus. It is the
final kinase in a 3-kinase sequence (mitogen-activated protein kinase)
Figure 16-32 Essential Cell Biology (© Garland Science 2010)
2. MAP kinase phosphorylates various downstream target proteins.
These target can include other protein kinase, and most important,
gene regulatory proteins that control gene expression. Changes in
gene expression and protein activity result in complex changes in
cell behaviors such as proliferation and differentiation
MAP Kinase
http://www.youtube.com/watch?v=bYioSvT33cA
Cancer parthway (Ras pathway)
http://www.youtube.com/watch?v=L9dsg0wJRR8&feature=r
elated
The MAP-Kinase (MAPK) signalling pathway (5 min)
http://www.youtube.com/watch?v=r7GoZ9vFCY8
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
RTKs can activate the PI-3-Akt signaling pathway
1.An extracellular survival signal, such as IGF (insulin-like growth
factor) family, activate an RTK, which recruits and activates PI-3kinase pathway to promote cell growth and survival
Figure 16-33 Essential Cell Biology (© Garland Science 2010)
2. PI3-kinase (phosphoinositide 3-kinase) is an enzyme which
can phoshphorylate inositol phospholipid in the plasma membrane
3. These phosphorylated lipids become docking sites for specific
intracellular signaling proteins, which relocate from cytosol to
membrane, where they can activate one another
The PI3K/AKT signalling pathway
http://www.youtube.com/watch?v=ewgLd9N3s-4&NR=1
PI3K/AKT Pathway and Cancer
http://www.youtube.com/watch?v=Jq4ZOu2UbqA&featu
re=related
Activated Akt promotes cell survival :
1. One of the relocated signaling proteins in the PI-3-kinase pathway
is the serine/threonine protein kinase Akt (also called protein kinase B
(PKB)). This pathway called PI-3-kinase-Akt singaling pathway
2. Akt promotes the growth and survival of may cell types often by
inactivating the signaling proteins it phosphorylates. It also stimulate
cells to grow in size
Figure 16-34 Essential Cell Biology (© Garland Science 2010)
3. Mechanism of PI-3-kinase-Akt singaling to promote cell survival:
Akt phosphorylates and inactivates a cytosolic protein, Bad, to
inhibits apoptosis in cells
Akt also stimulates cells to grow in size by
ativating Tor:
1.The binding of growth factor to and RTK
activates the PI-3-kinase-Akt signaling
pathway
2.Akt then indirectly activate Tor (by phosphorylating and inhibiting a protein that helps
to keep Tor shut down)
3. Tor, a serine/threonine kinase, stimulates
protein synthesis and inhibits protein
degradation
Figure 16-35 Essential Cell Biology (© Garland Science 2010)
Pop-up quiz:
1.Give two expalmes of G-protein-coupled singaling pathway
2.Give two examples of enzyme-coupled signaling pathway
Answere:
1.G-protein-coupled:
adenyl cyclase, C-AMP, PKA
PIP2, DAG & IP3
2.RTK:
Ras, MAPK
Ras, PI-3-kinase-Akt signaling
How we know: untangling cell signaling pathways
1. Cannot reveal the whole signaling pathway in a single
exp.
2. Needs to figure out piece by piece of how all the links in the
chain fit together, and how each contributes to the cell’s response
to and extracellular signal such as insulin
Exp:
1.Check the ‘stimulated phosphorylation’ :
Stimulate cells, separate all cellular proteins by gel, use antibody
to detect phosphorylated proteins
2. Close encounters:
Once the activated proteins have been identified, one can determine
which proteins interact with them using ‘co-immunoprecipitation’.
If two proteins are dragged down at the same time, very likely
they are interact with each other. In this way, researchers can
identify which proteins interact when an extracellular signal molecule
stimulates cells
Mutant proteins can help to determine exactly where an intracellular
signaling molecule binds
Mutant proteins can help to determine exactly where an intracellular
signaling molecule binds
Figure 16-36 Essential Cell Biology (© Garland Science 2010)
3. ‘Jamming the pathway’:
To test the function: use the recombinant DNA technology to
insert the gene in the form of constantly active form, to see if
this mimics the effect of the extracellular signal
e.g. A constitutively active form of Ras transmits a signal even
in the absence of an extracellular signal molecule
Figure 16-37 Essential Cell Biology (© Garland Science 2010)
On the contratory, scientist also needs to inactive
the protein or its gene and see weather the signaling
pathway is affected. e.g. to induce a ‘dominant-negtive’
mutant form of Ras, i.e. Ras binds to GTP too tightly to
be activated
4. ‘Ordering the pathway’:
Treat animals (fruit flies or nematode worms) with mutagen and
then looking for mutants in which a signaling pathway is not
functioning properly
Genetic analysis reveals the order in which intracellular signaling
proteins act in a pathway
Figure 16-38a Essential Cell Biology (© Garland Science 2010)
Figure 16-38b Essential Cell Biology (© Garland Science 2010)
Figure 16-38c Essential Cell Biology (© Garland Science 2010)
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
Some Enzyme-linked receptors activate a fast track to the nucleus
1.Some receptors use a more direct route to control gene expression
2.Cytokines binds to receptor, which activates a type of regulatory
proteins called STATS (signal transducers and activators of transcription)
Figure 16-39 Essential Cell Biology (© Garland Science 2010)
3. The signaling pathway of the cytokines:
Binding of a cytokine to its receptor causes associated tyrosine kinase
(called janus kinases, or JAKs) to cross phosphorylate and activate
one another
they phosphorylate the receptor protein on tyrosine
4. gene regulatory proteins, called STATs, attach to the
phosphotyrosine site of the receptor to be activated
STATs
dissociate from the receptor, dimerize, migrate to the nucleus
activate the transcription of specific target genes
5. example: hormone prolactin which stimulates breast cell to make
milk
The notch receptor itself is a transcription regulator
1.Notch receptor generate an even more direct signaling pathway
which controls the development of neural cells in Drosophila
Figure 16-40 Essential Cell Biology (© Garland Science 2010)
2. In this pathway, the receptor itself acts as a transcription regulator
3. Mechanism: when activated by the binding of Delta ,the Norch
receptor is cleaved. The released cytosolic tail of the receptor heads
to the nucleus to activate the appropriate set of
Notch-responsive genes
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
1. Plants and animals have been evolving independently for
more than a billion years
2. Like animals, plants make extensive use of transmembrane
cell-surface receptors, especially enzyme-coupled receptors.
e.g. the spindly weed Arabidopsis Thaliana (Fig 1-33) has hundreds
of genes encoding receptor serine/threonine kinase, but their
serine/threonine kinase receptor is very different to animal’s
3. Plant receptors trigger a large variety of cell signaling prosess
involves in plant growth, development and disease resistance
4. Plant don’t use RTKs, steroid-hormone-type nuclear receptors,
or c-AMP, they seem to use few GPCRs
5. One of the best-studied signaling pathways in plant mediates
the response of cells to ethylene- a gaseous hormone that regulates
a diverse array of development processes, including seed
germination and fruit ripening
ENZYME-COUPLED RECEPTORS
• Activated RTKs Recruit a Complex of
Intracellular Signaling Proteins
• Most RTKs Activate the Monomeric GTPase
Ras
• RTKs Activate PI 3-Kinase to Produce Lipid
Docking Sites in the Plasma Membrane
• Some Receptors Activate a Fast Track to the
Nucleus
• Multicellularity and Cell Communication
Evolved Independently in Plants and Animals
• Protein Kinase Networks Integrate
Information to Control Complex Cell
Behaviors
Signaling pathways can be highly interconnected (cross-talk)
Protein kinases in both pathways phosphorylate many proteins,
including proteins belonging to the other pathway
Figure 16-42 Essential Cell Biology (© Garland Science 2010)
Movie 16.7
Movie 16.8
Movie 16.9
Some intracellular signaling proteins serve to integrate incoming signals
Figure 16-43 Essential Cell Biology (© Garland Science 2010)