chapter 15
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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. - PowerPoint PPT PresentationTRANSCRIPT
CHAPTER 15Cell 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 receptor-mediated
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 glucosestorage 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 glucagonor 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 black-
and-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 theG 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 receptorto 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 muscleand 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 proteinsactivated 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 betweentwo 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 (receptor-mediated) 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 (mitochondria-
mediated) 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 isaccompanied by phagocytosis