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Chapter 14
Principles of Cell SignalingBy
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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• 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.
14.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular signals
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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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• Scaffolds increase the local concentration of signaling proteins.
• Scaffolds localize signaling pathways to sites of action.
14.8 Scaffolds increase signaling efficiency and enhance spatial organization of signaling
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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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• Most pathways contain multiple adaptive feedback loops to cope with signals of various strengths and durations.
14.10 Cellular signaling is remarkably adaptive
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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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• Isoforms may differ in:– function– susceptibility to regulation – expression
• Cells may express one or several isoforms to fulfill their signaling needs.
14.11 Signaling proteins are frequently expressed as multiple species
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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 protein’s 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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• 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.
14.15 Ca2+ signaling serves diverse purposes in all eukaryotic cells
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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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• 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.
14.16 Lipids and lipid-derived compounds are signaling molecules
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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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• Channels are selective for particular ions or for cations or anions.
• Channels regulate intracellular concentrations of regulatory ions, such as Ca2+.
14.18 Signaling through ion channel receptors is very fast
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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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• 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.
14.19 Nuclear receptors regulate transcription
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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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• Cells express several varieties of each class of proteins.
• Effectors are heterogeneous and initiate diverse cellular functions.
14.20 G protein signaling modules are widely used and highly adaptable
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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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• A common G-protein binding domain has not been identified among effector proteins.
• Effector proteins integrate signals from multiple G protein pathways.
14.21 Heterotrimeric G proteins regulate a wide variety of effectors
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14.22 Heterotrimeric G proteins are controlled by a regulatory GTPase
cycle• Heterotrimeric G proteins are
activated when the Gαsubunit binds GTP.
• GTP hydrolysis to GDP inactivates the G protein.
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• 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.
14.22 Heterotrimeric G proteins are controlled by a regulatory GTPase cycle
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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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• GAPs accelerate hydrolysis and deactivation.
• GDP dissociation inhibitors (GDIs) slow spontaneous nucleotide exchange.
14.23 Small, monomeric GTPbinding proteins are multiuse switches
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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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• Protein kinases may recognize the primary sequence surrounding the phosphorylation site.
• Protein kinases may preferentially recognize phosphorylation sites within folded domains.
14.24 Protein phosphorylation/ dephosphorylation is a major regulatory mechanism in the cell
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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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• 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.
14.25 Two-component protein phosphorylation systems are signaling relays
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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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• Phosphoprotein phosphatases may dephosphorylate:– phosphoserine/threonine– phosphotyrosine– or all three
• Phosphoprotein phosphatase specificity is often achieved through the formation of specific protein complexes.
14.27 Phosphoprotein phosphatases reverse the actions of kinases and are independently regulated
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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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• Ubiquitination can cooperate with other covalent modifications.
• Ubiquitination regulates signaling in addition to its role in protein degradation.
14.18 Covalent modification by ubiquitin and ubiquitinlike proteins is another way of regulating protein function
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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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• Wnts signal through multiple distinct receptors.
• Wnts suppress degradation of β-catenin, a multifunctional transcription factor.
14.29 The Wnt pathway regulates cell fate during development and other processes in the adult
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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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• Ligand binding promotes:– receptor oligomerization– autophosphorylation
• Signaling proteins bind to the phosphotyrosine residues of the activated receptor.
14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases
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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.