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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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http://../Ch.%2010/Lehninger%20Ch%2010.ppt

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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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