Chapter 14
Principles of Cell Signaling
By
Melanie H. Cobb & Elliott M. Ross
14.2 Cellular signaling is primarily
chemical
• Cells can detect both chemical and
physical signals.
• Physical signals are generally converted
to chemical signals at the level of the
receptor.
14.3 Receptors sense diverse stimuli but
initiate a limited repertoire of cellular
signals
• Receptors contain:
– a ligand-binding domain
– an effector domain
• Receptor modularity allows a wide
variety of signals to use a limited
number of regulatory mechanisms.
14.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular
signals
• Cells may express different receptors
for the same ligand.
• The same ligand may have different
effects on the cell depending on the
effector domain of its receptor.
14.4 Receptors are catalysts and
amplifiers
• Receptors act by increasing the rates of
key regulatory reactions.
• Receptors act as molecular amplifiers.
14.5 Ligand binding changes receptor
conformation
• Receptors can exist in active or inactive
conformations.
• Ligand binding drives the receptor
toward the active conformation.
14.6 Signals are sorted and integrated in
signaling pathways and networks
• Signaling pathways usually have
multiple steps and can diverge and/or
converge.
• Divergence allows multiple responses to
a single signal.
• Convergence allows signal integration
and coordination.
14.7 Cellular signaling pathways can be
thought of as biochemical logic circuits
• Signaling networks are composed of
groups of biochemical reactions.
– The reactions function as mathematical
logic functions to integrate information.
• Combinations of such logic functions
combine as signaling networks to
process information at more complex
levels.
14.8 Scaffolds increase signaling
efficiency and enhance spatial
organization of signaling
• Scaffolds:
– organize groups of signaling proteins
– may create pathway specificity by
sequestering components that have
multiple partners
14.8 Scaffolds increase signaling efficiency and enhance spatial organization of
signaling
• Scaffolds increase the local
concentration of signaling proteins.
• Scaffolds localize signaling pathways to
sites of action.
14.9 Independent, modular domains
specify protein-protein interactions
• Protein interactions may be mediated by
small, conserved domains.
• Modular interaction domains are
essential for signal transmission.
• Adaptors consist exclusively of binding
domains or motifs.
14.10 Cellular signaling is remarkably
adaptive
• Sensitivity of signaling pathways is
regulated to allow responses to change
over a wide range of signal strengths.
• Feedback mechanisms execute this
function in all signaling pathways.
14.10 Cellular signaling is remarkably
adaptive
• Most pathways contain multiple
adaptive feedback loops to cope with
signals of various strengths and
durations.
14.11 Signaling proteins are frequently
expressed as multiple species
• Distinct species (isoforms) of similar
signaling proteins expand the regulatory
mechanisms possible in signaling
pathways.
14.11 Signaling proteins are frequently expressed as multiple
species
• Isoforms may differ in:
– function
– susceptibility to regulation
– expression
• Cells may express one or several
isoforms to fulfill their signaling needs.
14.12 Activating and deactivating
reactions are separate and independently
controlled
• Activating and deactivating reactions
are usually executed by different
regulatory proteins.
• Separating activation and inactivation
allows for fine-tuned regulation of
amplitude and timing.
14.13 Cellular signaling uses both
allostery and covalent modification
• Allostery refers to the ability of a
molecule to alter the conformation of a
target protein when it binds
noncovalently to that protein.
• Modification of a protein’s chemical
structure is also frequently used to
regulate its activity.
14.14 Second messengers provide
readily diffusible pathways for information
transfer
• Second messengers can propagate
signals between proteins that are at a
distance.
• cAMP and Ca2+ are widely used second
messengers.
14.15 Ca2+ signaling serves diverse
purposes in all eukaryotic cells
• Ca2+ serves as a second messenger
and regulatory molecule in essentially
all cells.
14.15 Ca2+ signaling serves diverse purposes in all
eukaryotic cells
• Ca2+ acts directly on many target
proteins.
– It also regulates the activity of a regulatory
protein calmodulin.
• The cytosolic concentration of Ca2+ is
controlled by organellar sequestration
and release.
14.16 Lipids and lipid-derived compounds
are signaling molecules
• Multiple lipid-derived second
messengers are produced in
membranes.
• Phospholipase Cs release soluble and
lipid second messengers in response to
diverse inputs.
14.16 Lipids and lipid-derived compounds are signaling
molecules
• Channels and transporters are
modulated by different lipids in addition
to inputs from other sources.
• PI 3-kinase synthesizes PIP3 to
modulate cell shape and motility.
• PLD and PLA2 create other lipid second
messengers.
14.17 PI 3-kinase regulates both cell
shape and the activation of essential
growth and metabolic functions
• Phosphorylation of some lipid second
messengers changes their activity.
• PIP3 is recognized by proteins with a
pleckstrin homology domain.
14.18 Signaling through ion channel
receptors is very fast
• Ion channels allow the passage of ions
through a pore.
– This results in rapid (microsecond)
changes in membrane potential.
14.18 Signaling through ion channel receptors is
very fast
• Channels are selective for particular
ions or for cations or anions.
• Channels regulate intracellular
concentrations of regulatory ions, such
as Ca2+.
14.19 Nuclear receptors regulate
transcription
• Nuclear receptors modulate
transcription by binding to distinct short
sequences in chromosomal DNA known
as response elements.
14.19 Nuclear receptors regulate
transcription
• Receptor binding to other receptors,
inhibitors, or coactivators leads to
complex transcriptional control circuits.
• Signaling through nuclear receptors is
relatively slow, consistent with their
roles in adaptive responses.
14.20 G protein signaling modules are
widely used and highly adaptable
• The basic module is:
– a receptor
– a G protein
– an effector protein
14.20 G protein signaling modules are widely used and highly
adaptable
• Cells express several varieties of each
class of proteins.
• Effectors are heterogeneous and initiate
diverse cellular functions.
14.21 Heterotrimeric G proteins regulate
a wide variety of effectors
• G proteins convey signals by regulating
the activities of multiple intracellular
signaling proteins known as effectors.
• Effectors are structurally and
functionally diverse.
14.21 Heterotrimeric G proteins regulate a wide variety of
effectors
• A common G-protein binding domain
has not been identified among effector
proteins.
• Effector proteins integrate signals from
multiple G protein pathways.
14.22 Heterotrimeric G proteins are
controlled by a regulatory GTPase cycle
• Heterotrimeric G proteins are activated
when the Gα subunit binds GTP.
• GTP hydrolysis to GDP inactivates the
G protein.
14.22 Heterotrimeric G proteins are controlled by a regulatory
GTPase cycle
• GTP hydrolysis is slow, but is
accelerated by proteins called GAPs.
• Receptors promote activation by
allowing GDP dissociation and GTP
association.
– Spontaneous exchange is very slow.
• RGS proteins and phospholipase C-βs
are GAPs for G proteins.
14.23 Small, monomeric GTPbinding
proteins are multiuse switches
• Small GTP-binding proteins are:
– active when bound to GTP
– inactive when bound to GDP
• GDP/GTP exchange catalysts known as
GEFs (guanine nucleotide exchange
factors) promote activation.
14.23 Small, monomeric GTPbinding proteins are multiuse
switches
• GAPs accelerate hydrolysis and
deactivation.
• GDP dissociation inhibitors (GDIs) slow
spontaneous nucleotide exchange.
14.24 Protein phosphorylation/
dephosphorylation is a major regulatory
mechanism in the cell
• Protein kinases are a large protein
family.
• Protein kinases phosphorylate:
– Ser and Thr
– or Tyr
– or all three
14.24 Protein phosphorylation/ dephosphorylation is a major regulatory mechanism in
the cell
• Protein kinases may recognize the
primary sequence surrounding the
phosphorylation site.
• Protein kinases may preferentially
recognize phosphorylation sites within
folded domains.
14.25 Two-component protein
phosphorylation systems are signaling
relays
• Two-component signaling systems are
composed of sensor and response
regulator components.
14.25 Two-component protein phosphorylation systems are signaling
relays
• Upon receiving a stimulus, sensor
components undergo
autophosphorylation on a histidine (His)
residue.
• Transfer of the phosphate to an aspartyl
residue on the response regulator
serves to activate the regulator.
14.26 Pharmacological inhibitors of
protein kinases may be used to
understand and treat disease
• Protein kinase inhibitors are useful both:
– for signaling research
– as drugs
• Protein kinase inhibitors usually bind in
the ATP binding site.
14.27 Phosphoprotein phosphatases
reverse the actions of kinases and are
independently regulated
• Phosphoprotein phosphatases reverse
the actions of protein kinases.
14.27 Phosphoprotein phosphatases reverse the actions of kinases and are
independently regulated
• Phosphoprotein phosphatases may
dephosphorylate:
– phosphoserine/threonine
– phosphotyrosine
– or all three
• Phosphoprotein phosphatase specificity
is often achieved through the formation
of specific protein complexes.
14.18 Covalent modification by ubiquitin
and ubiquitinlike proteins is another way
of regulating protein function
• Ubiquitin and related small proteins may
be covalently attached to other proteins
as a targeting signal.
• Ubiquitin is recognized by diverse
ubiquitin binding proteins.
14.18 Covalent modification by ubiquitin and ubiquitinlike proteins is another way of regulating protein
function
• Ubiquitination can cooperate with other
covalent modifications.
• Ubiquitination regulates signaling in
addition to its role in protein
degradation.
14.29 The Wnt pathway regulates cell
fate during development and other
processes in the adult
• Seven transmembrane-spanning
receptors may control complex
differentiation programs.
• Wnts are lipid-modified ligands.
14.29 The Wnt pathway regulates cell fate during development and other processes in
the adult
• Wnts signal through multiple distinct
receptors.
• Wnts suppress degradation of βcatenin, a multifunctional transcription
factor.
14.30 Diverse signaling mechanisms are
regulated by protein tyrosine kinases
• Many receptor protein tyrosine kinases
are activated by growth factors.
• Mutations in receptor tyrosine kinases
can be oncogenic.
14.30 Diverse signaling mechanisms are regulated by protein tyrosine
kinases
• Ligand binding promotes:
– receptor oligomerization
– autophosphorylation
• Signaling proteins bind to the
phosphotyrosine residues of the
activated receptor.
14.31 Src family protein kinases
cooperate with receptor protein tyrosine
kinases
• Src is activated by release of intrasteric
inhibition.
• Activation of Src involves liberation of
modular binding domains for activationdependent interactions.
• Src often associates with receptors, including
receptor tyrosine kinases.
14.32 MAPKs are central to many
signaling pathways
• MAPKs are activated by Tyr and Thr
phosphorylation.
• The requirement for two
phosphorylations creates a signaling
threshold.
• The ERK1/2 MAPK pathway is usually
regulated through Ras.
14.33 Cyclin-dependent protein kinases
control the cell cycle
• The cell cycle is regulated by cyclindependent protein kinases (CDKs).
• Activation of CDKs involves:
– protein binding
– dephosphorylation
– phosphorylation
14.34 Diverse receptors recruit protein
tyrosine kinases to the plasma membrane
• Receptors that bind protein tyrosine
kinases use combinations of effectors
similar to those used by receptor
tyrosine kinases.
• These receptors often bind directly to
transcription factors.