The Cell Ch.13
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Transcript of The Cell Ch.13
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Signaling Molecules and Their ReceptorsFunctions of cell surface receptorsPathways of Intracellular Signal TransductionProgrammed Cell Death
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Modes of Cell-Cell Signaling
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Fig.12-2Six General Types of Signal Transducers
Signaling Molecules
Cell surface receptors
Pathways of Intracellular Signal Transduction
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Signaling Molecules
steroid hormonesNO and COneurotransmitters
peptide hormones, neuropeptides, and growth factorseicosanoids
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Human steroid hormones
sex hormones (synthesized in gonads or placenta)
testosterone
Cholesterol estrogen
progesterone
corticosteroids (synthesized in the cortex of adrenal gland)
glucocroticoids
mineralocorticoids
Ecdysone (insect hormone)
Brassinosteroids (plant-specific steroid hormones)
St t f St id H Th id H
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Structure of Steroid Hormones, Thyroid Hormone,Vitamin D3, and Retinoic Acid
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E t A ti
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Estrogen Action
histone acetyltransferase
Gene Regulation by the Thyroid Hormone Receptor
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Gene Regulation by the Thyroid Hormone Receptor
histone deacetylase
Hi t t l ti
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Fig. 6-32 Histone acetylation
Histone acetylation is characteristic of
actively transcribed chromatin and may
weaken the binding of histones to DNA or
alter their interactions with other proteins
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S th i f Nit i O id
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Synthesis of Nitric Oxide
Membrane Form of Guanylyl Cyclase
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kidney intestinal epithelial cells
Membrane Form of Guanylyl Cyclase
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NO activates guanylyl cyclase
Structure of Representative Neurotransmitters
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Structure of Representative Neurotransmitters
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Figure 13.6 Structure of Representative Neurotransmitters (Part 2)
Peptides as Hormones
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Peptides as Hormones
Peptide hormones
insulin, glucagon, FSH, and prolactin
Neuropeptides
oxytocin, vasopressin, enkephalins, and endorphins.
Polypeptide growth factors
NGF (nerve growth factor)1950EGF (epidermal growth factor)
PDGF (platelet-derived growth factor)
cytokines
i li
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Fig.23-5 insulin
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Structure of Epidermal Growth Factor (EGF)
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Structure of Epidermal Growth Factor (EGF)
Synthesis and Structure of Eicosanoids
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lipoxygenasescycloxygenase
Synthesis and Structure of Eicosanoids
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thromboxane synthase
The eicosanoids are rapidly broken down and thereforeact locally in autocrine orparacrine signaling pathway.
Structure of Plant Hormones
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Structure of Plant Hormones
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arachidonic acid
prostaglandin H2 leukotriene B4
prostaglandin A2 thromboxane A2
cyclooxygenase lipooxygenase
thromboxane synthase
aspirin
reduces inflammation and pain aspirin also reduces platelet aggregation and blood clotting
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Functions of Cell Surface Receptors
G protein-coupled receptorsReceptor protein-tyrosine kinaseNonreceptor protein-tyrosine kinase
G Protein-Coupled Receptor
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G Protein Coupled Receptor
The largest family of cell surface receptorsMore than a thousand such G protein coupled receptors are identified
Hormonal Activation of Adenylyl Cyclase
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Hormonal Activation of Adenylyl Cyclase
heterotrimeric G proteins
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epinephrine = adrenaline
b-adrenergic receptor
Gs: GTP-binding stimulatory G protein
Gs is held to the membrane by a covalentlAttached palmitoyl group
Regulation of G Proteins
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Regulation of G Proteins
In the inactive state, the subunit is bound to GDP ina complex with b and .
Hormone binding induces an interaction of the
receptor with the G protein, stimulating the releaseof GDP and the exchange of GTP.
Activity of the subunit isterminated by hydrolysis ofthe bound GTP, and theinactive GDP-bound
subunit then reassociateswith the b complex.
Mammalian genome encode at least 20 subunits, 6 b
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Heart muscle cells acetylcholine receptor
Gi Gi the Gib subunits act directly to open K+ channels in the plasmamembrane, which has the effect of slowing heart muscle contraction.
g ,subunits, and 11 subunits
heart muscle cells
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The effect of acetylcholine on heart muscle cells is to
a. stimulate one contraction.b. increase the rate of beating.
c. decrease the rate of beating.d. relax the heart.
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Neurotransmitters act by binding to receptors that are
a. ligand-gated ion channels.
b. G protein linked receptors.c. tyrosine-kinase receptors.d. Both a and b
Receptor Protein-Tyrosine Kinases
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ecep o o e y os e ases
insulin receptorEGF receptor
a dimer of two pairs ofpolypeptide chains
Dimerization and Autophosphorylation of Receptor Protein-T i Ki
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p p y pTyrosine Kinases
1) increases protein kinase activity2) creates binding sites
ligand induced dimerization
autophosphorylation by
cross-phosphorylation
Association of Downstream Signaling Molecules with
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g gReceptor Protein-Tyrosine
The effects of SH2-phosphotyrosine binding
1) Lead to their association with other proteins2) Pormote phosphorylation
3) Stimulate enzymatic activities
Figure 13.16 Complex between an SH2 Domain and aPh h t i P tid Ki
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g pPhosphotyrosine Peptide Kinases
Cytokine Receptors
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JAK
Src
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QuickTime M
TIFF (LZW)YeC
Receptors for erythropoietin, growth hormones, and IL-13
Receptors for IL-3, IL-5, and GM-CSF share a commonchain CD131 orbc
Receptors for IL-2, IL-4, IL-7, IL-9 and IL-15
IFN-, b, and receptorsIL-10 receptor
TNF receptors I and IICD40, Fas (Apo1), CD30, CD27Nerve growth factor receptor
CCR1-5, CXCR1-4
Class I cytokinereceptor(hematopoietin-
receptor family)
Class IIcytokinereceptors
TNF-receptorfamily
Chemokinereceptorfamily
Src family, which consists of Src and eight closely related proteins
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Annu.Rev.Cell Dev.Biol.13:513.1997
Other Receptor-Linked Enzymatic Activities
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protein tyrosine phosphataseTGF-bguanylyl cyclases
Other Receptor Linked Enzymatic Activities
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some Src
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QuickTime MTIFF (LZW)Y
eC
CD45RA
CD45RO
Splicing of the CD45 gene transcript in nave T cellsincludes the A, B,and C exons
In memory/effector T cells, splicing of the CD45transcript
Excludes the A, B,and C exons
Receptor with protein serine/threonine kinase activities
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transforming growth factor-b
Both receptor components have a
serine/threonine protein kinase domain in the
cytoplasmic region
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Intracellular Signal Transduction
cAMP and cGMP
Phospholipid and Ca2+
Ras, Raf, and MAP kinaseThe JAK/STAT
Intracellular signaling was first elucidated by studies of the action of
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g g yepinephrine
Synthesis and Degradation of cAMP
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Regulation of Protein Kinase A
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g
phosphorylate serine/threonine residues
Regulation of Glycogen Metabolism by Protein Kinase A
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Fig. 12-16 Lehninger
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The chain of reactions leading from epinephrinereceptor
to glycogen phosphorylase provides a good illustration of
signal amplification during intracellular signal transduction.
Cyclic AMP-Inducible Gene Expression
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cAMP response element
CRE binding protein
Regulation of Protein Phosphorylation by Protein Kinase
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A and Protein Phosphatase 1
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How would overexpression of protein phosphatase 1
affect the induction of cAMP-inducible genes in response
to hormone stimulation of appropriate target cells? Would
protein phosphatase 1 affect the function of cAMP-gated
ion channels involved in odorant reception?
Fig. 12-36 Lehninger cAMP can also directly regulate ion channels
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Role of cGMP in Photoreception
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Light Induced Hyperpolarization of Rod Cells
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[cGMP]
cGMP gated ion channel close
Na+K+ ATPase hyperpolize plasma
membrane
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the chromophore 11-cis retinal
The First Stage in Visual Transduction
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When a proton is absorbed, the energy convert 11 cis-retinal to all-trans-retin
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500 nM
Hydrolysis of PIP2
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phosphatidylinositol 4,5-bisphosphate
One of the most widespread pathways of intracellular signaling is based on the
second messengers derived form PIP2
Activation of Phospholipase C by Protein-Tyrosine Kinases
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Fig.12-19 Lehninger hormone-activated phospholipase C and IP3
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PIP2
Structure of a Phorbol Ester
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Ca2+ Mobilization by IP3
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ligand-gated Ca2+ channel
0.1 mM
Fig. 13-28 Function of CalmodulinMany of the effects of Ca2+ are mediated by the Ca2+ binding protein calmodulin
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0.1mM 0.5mM
Many of the effects of Ca2 are mediated by the Ca2 binding protein calmodulin
Fig. 15-41. The activation of CaM-kinase II
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Cyclic AMP-Inducible Gene Expression
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cAMP response element
CRE binding protein
Regulation of Intracellular Ca2+ in Electrically Excitable Cells
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membrane depolyrization
Plasma membrane voltage-gated Ca2+ channel open
Intracellular Ca2+
ryanodine receptors open, more Ca2+
Release of neurotransmitters
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ligand -gated(IP3)
ligand -gated
(Ca
2+
)
voltage -gated
P-type Ca2+pump
P-type Ca2+pump
Activity of PI 3-Kinase
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phosphatidylinositol 3,4,5-triphosphate
Activation of the Akt protein Kinase
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Activation of the ERK MAP Kinases
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Figure 13.33 Regulation of Ras Proteins
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Guanine nucleotide exchange facto
GTPase-activating proteins
Figure 13.34 Ras Activation Downstream of Receptor
P t i T i Ki
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Protein-Tyrosine Kinases
Figure 13.35 Induction of Immediate-Early Genes by ERK
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Figure 13.36 Pathways of MAP Kinase Activation in MammalianCells
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Figure 13.37 A Scaffold Protein for the JNK MAP Kinase Cascade
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Figure 13.38 The JAK/STAT Pathway
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signal transducers and
activators of transcription
Figure 13.39 Integrin Signaling
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focal adhesion kinase
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Figure 13.40 Regulation of Actin Remodeling by Rho FamilyProteins (Part 1)
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Figure 13.40 Regulation of Actin Remodeling by RhoFamily Proteins (Part 2)
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Figure 13.41 Regulation of Myosin Light ChainPhosphorylation by Rho
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Signaling in Development and Differentiation
Figure 13.42The Drosophila Compound Eye800 individual units by
di t ll ll i li i diff ti ti
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y
Scanning electron micrograph
8 photoreceptor neurons and 12lens cells
direct cell-cell signaling in differentiation
Figure 13.43 Induction of R7 Differentiation
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Figure 13.44 Induction of the Vulva in C. elegans
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(EGF)
Figure 13.44 Induction of the Vulva in C. elegans
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Figure 13.45 Hedgehog Signaling
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Figure 13.46 The Wnt Pathway
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Figure 13.47 Notch Signaling
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Apoptosis (Programmed Cell Death)
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Programmed cell death is an active process characterized by a distinctmorphological change known as apoptosis
Characterization of apoptosis
Ced-9, Ced-4, Ced-3, caspases
Bcl-2
Death signal and its receptors -Fas
Survival signal -
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finally, apoptotic bodies are formed
Chromatin Condensation and Nuclear Fragmentation
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caspase cleaves an DNase inhibitor DNA fragmentation
caspase cleaves nuclear lamins
fragmentation of nucleuscaspase cleaves cytoskeleton membrane blebbing and cell fragmentation
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Science281:1322. 1998
Ced-4 and its mammalian homolog (Apa-1) bind to caspasesand promote their activation
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Science281:1322. 1998
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Science281:1322. 1998
Other members of the Bcl-2 family,induce caspase activationand promote cell death
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Science281:1322. 1998
Regulators and Effectors of Apoptosis
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Cell Death Receptors
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The PI 3-Kinase Pathway and Cell Survival
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Key Experiment 13.1 The Src Protein-Tyrosine Kinase
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Molecular Medicine 13.1 Cancer: Signal Transduction and therasOncogenes
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