CHAPTER 15
Cell Signaling and Signal
Transduction: Communication
Between Cells
Introduction
• Cells must respond adequately to external
stimuli to survive.
• Cells respond to stimuli via cell signaling.
• Some signal molecules enter cells; others bind
to cell-surface receptors.
15.1 The Basic Elements of Cell
Signaling Systems (1)
• Extracellular messenger molecules transmit
messages between cells.
– In autocrine signaling, the cell has receptors on its
surface that respond to the messenger.
– During paracrine signaling, messenger molecules
travel short distances through extracellular space.
– During endocrine signaling, messenger molecules
reach their target cells through the bloodstream.
Types of intercelular signaling
The Basic Elements of Cell Signaling
Systems (2)
• Receptors on or in target cells receive the
message.
– Some cell surface receptors generate an
intracellular second messenger through an
enzyme called an effector.
– Other surface receptors recruit proteins to their
intracellular domains.
Overview of
signaling pathways
The Basic Elements of Cell Signaling
Systems (3)
• Signaling pathways consist of a series of
proteins.
– Each protein in a pathway alters the conformation
of the next protein.
– Protein conformation is usually altered by
phosphorylation.
– Target proteins ultimately receive a message to
alter cell activity.
– This overall process is called signal transduction.
A signal transduction pathway
15.2 A Survey of Extracellular
Messengers and Their Receptors (1)
• Extracellular messengers include:
– Small molecules such as amino acids and their
derivatives.
– Gases such as NO and CO
– Steroids
– Eicosanoids, which are lipids derived from fatty
acids.
– Various peptides and proteins
A Survey of Extracellular Messengers
and Their Receptors (2)
• Receptor types include:
– G-protein coupled receptors (GPCRs)
– Receptor protein-tyrosine kinases (RTKs)
– Ligand gated channels
– Steroid hormone receptors
– Specific receptors such as B-and T-cell receptors
15.3 G Protein-Coupled Receptors and
Their Second Messengers (1)
• G protein-coupled receptors (GPCRs) are
numerous.
• GPCRs have seven transmembrane domains
and interact with G proteins.
A GPCR and a G protein
A GPCR and a G protein
Examples of GPCRs and their ligands
G Protein-Coupled Receptors and Their
Second Messengers (2)
• Signal Transduction by G Protein-Coupled
Receptors
– Ligand binding on the extracellular domain
changes the intracellular domain.
– Affinity for G proteins increases, and the receptor
binds a G protein intracellularly.
– GDP is exchanged for GTP on the G protein,
activating the G protein.
– One ligand-bound receptor can activate many G
proteins.
Mechanism of receptormediated
activation/inhibition by G
proteins
G Protein-Coupled Receptors and Their
Second Messengers (3)
• Termination of the Response
– Desensitization – by blocking active receptors
from turning on additional G proteins.
– G protein-coupled receptor kinase (GRK) activates
a GPCR via phosphorylation.
– Proteins called arrestins compete with G proteins
to bind GPCRs.
– Termination of the response is accelerated by
regulators of G protein signaling (RGSs).
G Protein-Coupled Receptors and Their
Second Messengers (4)
• Bacterial Toxins, such as cholera toxin and
pertussis virulence factors, target GPCRs and G
proteins.
• Second Messengers
– The Discovery of Cyclic AMP
• It is a second messenger, which is released into the
cytoplasm after binding of a ligand.
• Second messengers amplify the response to a single
extracellular ligand.
The localized formation of cAMP
G Protein-Coupled Receptors and Their
Second Messengers (5)
• Phosphatidylinositol-Derived Second
Messengers
– Some phospholipids of cell membranes are
converted into second messengers by activated
phospholipases.
• Phosphatidylinositol Phosphorylation
– Phosphoinositides (PI) are derivatives of
phosphatodylinositol.
Phospholipid-based second messengers
G Protein-Coupled Receptors and Their
Second Messengers (6)
• Phosphatidylinositol-specific phospholipase C produces second messengers derived from
phosphatidylinositol-inositol triphosphate
(IP3) and diacylglycerol (DAG).
• DAG activates protein kinase C, which
phosphorylates serine and threonine residues
on target proteins.
• The phosphorylated phosphoinositides form
lipid-binding domains called PH domains.
The generation of second messengers as a result
of breakdown of PI
G Protein-Coupled Receptors and Their
Second Messengers (7)
• One IP3 receptor is a
calcium channel located
at the surface of the
smooth endoplasmic
reticulum.
• Binding of IP3 opens the
channel and allows Ca2+
ions to diffuse out.
Examples of responses mediated by
Protein Kinase C
Cellular responses elicited by adding IP3
G Protein-Coupled Receptors and Their
Second Messengers (8)
• Regulation of Blood Glucose Levels
– Different stimuli acting on the same target cell
may induce the same response.
• Glucagon and epinephrine bind to different receptors
on the same cell.
• Both hormones stimulate glucoses breakdown and
inhibit its synthesis.
• cAMP is activated by the G protein of both hormone
receptors
– Responses are amplified by signal cascades.
The reactions that lead to glucose
storage or mobilization
G Protein-Coupled Receptors and Their
Second Messengers (9)
• Glucose Metabolism: An Example of a
Reponse Induced by cAMP
– cAMP is synthesized by adenylyl cyclase.
– cAMP evokes a reaction cascade that leads to
glucose mobilization.
– Once formed, cAMP molecules diffuse into the
cytoplasm where they bind a cAMP-dependent
protein kinase (protein kinase A, PKA).
Formation of cAMP from ATP
The response by a liver cell to glucagon
or epinephrine
G Protein-Coupled Receptors and Their
Second Messengers (10)
• Other Aspects of cAMP Signal Transduction
Pathways
– Some PKA molecules phosphorylate nuclear
proteins.
– Phosphorylated transcription factors regulate
gene expression.
– Phosphatases halt the reaction cascade.
– cAMP is produced as long as the external stimulus
is present.
The variety of processes that can be affected by
changes in [cAMP]
Examples of hormone-induced responses
mediated by cAMP
PKA-anchoring protein signaling
G Protein-Coupled Receptors and Their
Second Messengers (11)
• The Role of GPCRs in Sensory Perception
– Rhodopsin is a photosensitive protein for blackand-white vision that is also a GPCR.
– Several color receptors are GPCRs.
– Odorant receptors in the nose are GPCRs.
– Taste receptors for bitter and some sweet flavors
are GPCRs.
The Human Perspective: Disorders Associated
with G Protein-Coupled Receptors (1)
• Several disorders are caused by defects in
receptors or G proteins.
• Loss of function mutations result in
nonfunctional signal pathways.
– Retinitis pigmentosa, a progressive degeneration
of the retina, can be caused my mutations in
rhodopsin’s ability to activate a G protein.
Transmembrane receptor responsible for
causing human diseases
Human diseases
linked to the G
protein pathway
The Human Perspective: Disorders Associated
with G Protein-Coupled Receptors (2)
• Gain of function mutations may create a
constitutively activated G protein.
– Some benign thyroid tumors are caused by a
mutation in a receptor.
• Certain polymorphisms in G protein-related
genes may result in an increased susceptibility
to asthma or high blood pressure, as well as
decreased susceptibility to HIV.
15.4 Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (1)
• Protein-tyrosine kinases phosphorylate
tyrosine residues on target proteins.
• Protein-tyrosine kinases regulate cell growth,
division, differentiation, survival, and
migration.
• Receptor protein-tyrosine kinases (RTKs) are
cell surface receptors of the protein-tyrosine
kinase family.
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (2)
• Receptor Dimerization
– Results from ligand binding.
– Protein kinase activity is activated.
• Tyrosine kinase phosphorylates another subunit of the
receptor (autophosphorylation).
• RTKs phosphorylate tyrosines within phosphotyrosine
motifs.
Steps in the
activation of RTK
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (3)
• Phosphotyrosine-Dependent Protein-Protein
Interactions
– Phosphorylated tyrosines bind effector proteins
that have SH2 domains and PTB domains.
– SH2 and PTB domain proteins include:
• Adaptor proteins that bind other proteins.
• Docking proteins that supply receptors with other
tyrosine phosphorylation sites.
• Signaling enzymes (kinases) that lead to changes in cell.
• Transcription factors
The interaction between SH2 domain and a
peptide contain a phosphotyrosine
A diversity of signaling proteins
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (4)
• The Ras-MAP Kinase Pathway
– Ras is a G protein embedded in the membrane by
a lipid group.
– Ras is active when bound to GTP and inactive
when bound to GDP.
The structure of a G protein and the
G protein cycle
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (5)
• Ras-MAP kinase pathway (continued)
– Accessory proteins play a role:
• GTPase-activating proteins (GAPs) shorten the active
time of Ras.
• Guanine nucleotide-exchange factors (GEFs) stimulate
the exchange of GDP for GTP.
• Guanine nucleotide-dissociation inhibitors (GDIs)
inhibit release of GDP.
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (6)
• Ras-MAP kinase pathway (continued)
– The Ras-MAP kinase cascade is a cascade of
enzymes resulting in activation of transcription
factors.
– Adapting the MAP kinase to transmit different
types of information:
• End result differs in different cells/situations.
• Specificity of the MAP kinase response due to
differences in the types of kinases participating and
differences in spatial organization of components.
The steps of a generalized
MAP kinase cascade
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (7)
• Signaling by the Insulin Receptor
– Insulin regulates blood glucose levels by increasing
cellular uptake of glucose.
– The insulin receptor is a protein-tyrosine kinase
• Autophosphorylated receptor associates with insulin
receptor substrate proteins (IRSs).
• IRSs bind proteins with SH2 domains, which activate
downstream signal molecules.
• SH2 domain-containing proteins are kinases that
phosphorylate a lipid, PI 3-kinase (PI3K).
The response of the insulin receptor
to ligand binding
The role of tyrosine-phosphorylated IRS in
activating a variety of signaling pathways
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (8)
• Glucose Transport
– PKB regulates glucose uptake by GLUT4
transporters.
• GLUT4 transporters reside in intracellular membrane
vesicles.
• Vesicles fuse with the membrane in response to ligand
binding to the IR.
– Diabetes mellitus is caused by defects in insulin
signaling and Type 2 diabetes is caused by gradual
insensitivity to insulin.
Regulation of glucose uptake in muscle
and fat cells by insulin
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (9)
• Insulin Signaling and Lifespan
– Several studies demonstrate that the lifespan can
be increased by decreasing the level of insulin.
– Human who live along life show high insulin
sensitivity.
– Laboratory studies show that calorie restriction
leads to decreased insulin levels and increased
insulin sensitivity.
Protein-Tyrosine Phosphorylation as a
Mechanism for Signal Transduction (10)
• Signaling Pathways in Plants
– Plants lack cyclic nucleotides and RTKs.
– Plants have protein kinases that phosphorylate
histidine residues.
• The downstream cascade is similar to MAP kinase
cascade.
• The target of the cascade is usually transcription
factors.
15.5 The Role of Calcium as an
Intracellular Messenger (1)
• Cytoplasmic calcium levels are determined by
events within a membrane.
– Calcium levels are low in the cytosol because it is
pumped out into the extracellular space and the
membrane is highly impermeable to the ion.
– Calcium channels can be transiently opened by
action potential or calcium itself.
– Calcium binds to calcium-binding proteins (such
as calmodulin), which affects other proteins.
Experimental demonstration of localized release
of intracellular Ca2+
Calcium-induced calcium release
Calcium wave in a starfish egg
Examples of mammalian proteins
activated by Ca2+
The Role of Calcium as an
Intracellular Messenger (2)
• Recent research indicates a phenomenon
called store-operated calcium entry (SOCE).
• During SOCE the depleted calcium levels
trigger a response that lead to opening of
calcium channels.
• The mechanism responsible for SOCE is a
signaling system between the ER and plasma
membrane.
A model for store-operated calcium entry
Calmodulin
The Role of Calcium as an
Intracellular Messenger (3)
• Regulating Calcium Concentrations in Plant
Cells
– Cytosolic calcium changes in response to several
stimuli, including light, pressure, gravity, and
hormones.
– Calcium signaling aids in decreasing turgor
pressure in guard cells.
A model of the role of Ca2+ in guard cell closure
15.6 Convergence, Divergence and Crosstalk
Among Different Signaling Pathways (1)
• Signaling pathways can converge , diverge,
and crosstalk as follows:
– Signals form unrelated receptors can converge to
activate a common effector.
– Identical signals can diverge to activate a variety
of effectors.
– Signals can be passed back and forth between
pathways as a result of crosstalk.
Examples of convergence, divergence, and
crosstalk among signal transduction pathways
Convergence, Divergence and Crosstalk Among
Different Signaling Pathways (2)
• Convergence – GPCRs, receptor tyrosine
kinases, and integrins bind to different ligands
but they all can lead to a docking site for Gbr2.
Convergence of signals transmitted from a
GPCR, an integrin, and receptor tyrosine kinase
Convergence, Divergence and Crosstalk Among
Different Signaling Pathways (3)
• Divergence – all of the examples of signal
transduction so far are evidence of divergence
of how a single stimulus sends signals along a
variety of different pathways.
Convergence, Divergence and Crosstalk Among
Different Signaling Pathways (4)
• Crosstalk – more and more crosstalk is found
between signaling pathways:
– cAMP can block signals transmitted through the
MAP kinase cascade.
– Ca2+ and cAMP can influence each other’s
pathways.
An example of crosstalk between
two major signaling pathways
15.7 The Role of NO as an
Intracellular Pathway
• Nitric oxide (NO) is both an extracellular and
intercellular messenger with a variety of
functions.
• NO is produced by nitric oxide synthase.
– NO stimulates guanylyl cyclase, making cGMP.
– cGMP decreases cytosolic calcium and relaxes
smooth muscle.
– NO also plays a role in male arousal.
Signal transduction by means of NO and cGMP
15.8 Apoptosis (Programmed Cell
Death) (1)
• Apoptosis is an ordered process involving cell
shrinkage, loss of adhesion to other cells,
dissection of chromatin, and engulfment by
pahgocytosis.
A comparison of normal and apoptotic cells
Apoptosis (Programmed Cell
Death) (2)
• Apoptotic changes are activated by proteolytic
enzymes called caspases, which target:
– Protein kinases, some of which cause detachment
of cells.
– Lamins, which line the nuclear envelope.
– Proteins of the cytoskeleton
– Caspase activated DNase (CAD)
Apoptosis (Programmed Cell
Death) (3)
• The Extrinsic Pathway of Apoptosis
– It is initiated by external stimuli:
• Tumor necrosis factor (TNF) is detected by a TNF cell
surface receptor.
• Bound TNF receptors recruit “procaspases” to the
intracellular domain of the receptor.
• Procaspases convert other procaspases to caspases.
• Caspases activate executioner caspases, leading to
apoptosis.
The extrinsic
(receptormediated)
pathway of
apoptosis
Apoptosis (Programmed Cell
Death) (4)
• The Intrinsic Pathway of Apoptosis
– It is initiated by intracellular stimuli.
• Proapoptotic proteins stimulate mitochondria to leak
proteins, mostly cytochrome c.
• Release of apoptotic mitpchondrial proteins irreversibly
commits the cell to apoptosis.
The intrinsic
(mitochondriamediated) pathway
of apoptosis
Release of cytochrome c and nuclear
fragmentation during apoptosis
Apoptosis (Programmed Cell
Death) (5)
• Antiapoptotic proteins promote survival.
• Cell fate depends on the balance between
pro- and anti-apoptotic signals.
• Apoptotic cell death occurs without spilling
cellular contents to prevent inflammation.
• Apoptotic cells are cleared by phagocytosis.
Clearance of apoptotic cells is
accompanied by phagocytosis