Principles of Cell Signaling

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Chapter 14

• Principles of Cell Signaling
• By
• Melanie H. Cobb Elliott M. Ross

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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.

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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.

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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.

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14.4 Receptors are catalysts and amplifiers

• Receptors act by increasing the rates of key
  regulatory reactions.
• Receptors act as molecular amplifiers.

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14.5 Ligand binding changes receptor conformation

• Receptors can exist in active or inactive
  conformations.
• Ligand binding drives the receptor toward the
  active conformation.

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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.

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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.

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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

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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.

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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.

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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.

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14.10 Cellular signaling is remarkably adaptive

• Most pathways contain multiple adaptive feedback
  loops to cope with signals of various strengths
  and durations.

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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.

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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.

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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.

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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 proteins chemical structure is
  also frequently used to regulate its activity.

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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.

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14.15 Ca2 signaling serves diverse purposes in
all eukaryotic cells

• Ca2 serves as a second messenger and regulatory
  molecule in essentially all cells.

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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.

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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.

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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.

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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.

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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.

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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.

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14.19 Nuclear receptors regulate transcription

• Nuclear receptors modulate transcription by
  binding to distinct short sequences in
  chromosomal DNA known as response elements.

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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.

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14.20 G protein signaling modules are widely used
and highly adaptable

• The basic module is
• a receptor
• a G protein
• an effector protein

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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.

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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.

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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.

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14.22 Heterotrimeric G proteins are controlled by
a regulatory GTPase cycle

• Heterotrimeric G proteins are activated when the
  Ga subunit binds GTP.
• GTP hydrolysis to GDP inactivates the G protein.

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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-ßs are GAPs for
  G proteins.

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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.

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14.23 Small, monomeric GTPbinding proteins are
multiuse switches

• GAPs accelerate hydrolysis and deactivation.
• GDP dissociation inhibitors (GDIs) slow
  spontaneous nucleotide exchange.

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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

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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.

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14.25 Two-component protein phosphorylation
systems are signaling relays

• Two-component signaling systems are composed of
  sensor and response regulator components.

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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.

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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.

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14.27 Phosphoprotein phosphatases reverse the
actions of kinases and are independently regulated

• Phosphoprotein phosphatases reverse the actions
  of protein kinases.

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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.

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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.

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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.

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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.

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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 ß-catenin, a
  multifunctional transcription factor.

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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.

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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.

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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 activation-dependent
  interactions.
• Src often associates with receptors, including
  receptor tyrosine kinases.

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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.

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14.33 Cyclin-dependent protein kinases control
the cell cycle

• The cell cycle is regulated by cyclin-dependent
  protein kinases (CDKs).
• Activation of CDKs involves
• protein binding
• dephosphorylation
• phosphorylation

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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.