Copyright © 2005 Pearson Prentice Hall, Inc

Copyright © 2005 Pearson Prentice Hall, Inc.

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Cell Signaling• General Principles of Cell Signaling

– signaling cell => signaling molecule binds to receptor molecule on target cell

Signaling Distances: => Four Types of Signaling F.16-3

• Endocrine• Paracrine• Neuronal• Contact Dependent

• T16-1 • testosterone, • TGF-b, acetylcholine, • Delta


Cell Signaling• Receptor:

– Each Target Cell Responds to Limited Set of Signals

(origin of complexity)

– Must have receptor molecule for the signaling molecule

(thousands of receptors)

– Different receptors for same signal on different cells

F16-5 A & C or F16-5 B & C

•


Cell Signaling• Intracellular

Signaling Pathways: – Same receptor

molecule can interact w/many intracellular relay systems so same signal & same receptor => different effects in different cells

F16-5A & B

– Same relay system many act on many different intracellular targets

F16-7


Cell Signaling

• Target Cell Action:Depends upon ---- F16-6

– Signals That are Present– Receptors That Target Cell Synthesizes– Intracellular Relay Systems = Signaling Cascades

That Target Cell Synthesizes– Intracellular Targets That Target Cell Synthesizes

F16-8

• Any target cell type at any one time has only a subset of all possible – Receptors, – Intracellular Relay Systems, – Intracellular Targets


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Cell Signaling

• Signaling Cascades: Critical Functions

• pp. 539 & 540

• (be able to apply each function to components of the signaling cascades we study)

• Transduce Signal• Relay signal from point of reception to

point of response production• Amplify F16-29

• Distribute signal to >1 process simultaneously

• Modulate signal to fit other internal & external conditions


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Cell Signaling

• Extracellular Signaling Molecules: • Two Types of Extracellular Signaling Molecules• Based on Ability to Cross Plasma Membrane

F.16-9

• Cross Plasma Membrane (hydrophobic)– NO directly activate intracellular enzymes

F16-10

• vascular endothelial cells release NO• activates guanyl cyclase in smooth muscle

=> relaxation => vasodilation• guanyl cyclase: GTP = cGMP• nitroglycerine, erection, Viagra (blocks cGMP

reakdown)– Steroid Hormones F16-11 & 12

•


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16_10_Nitric_oxide.jpg


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16_12_cortisol.jpg


Cell Signaling

• Ligand for Cell Surface Receptor • (hydrophilic: don’t cross plasma membrane)

F16-1

– Ion-Channel-Linked Receptors F16-14A

• convert chemical to electrical signals

– G-protein-linked Receptors F16-14B, & F16-17

• ligand binding => G-Protein activation by exchange bound GDP for GTP

• Common structure = 7-pass membrane protein F16-16

– Enzyme-Linked ReceptorsF16-14C


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Cell Signaling

• Intracellular Signaling Molecules – Many are Molecular Switches– switched on by signaling molecule, must also be turned

off

• Most common switching mechanisms T16-2 nicotine, morphine & heroin

– phosphorylation F16-15A

– signal activated kinase; – dephosphorylation – phosphatase

– GTP binding proteins: F16-15B

– GDP bound = inactive, – GTP bound = active


Cell SignalingG-Protein Linked Receptors

• Largest family of cell-surface receptors – 100s of members

• 7-pass Transmembrane Proteins F16-16

• Ligand binding Activates G-Protein subunits

F16-17

Inactivated by hydrolysis of its own bound GTP F16-18 cholera toxin prevents this; G protein stays on => water & ion loss


16_18_Gprot_subunit.jpg


Cell SignalingG-Protein Linked Receptors

• Action mechanisms– Some regulate ion channels F16-19

• Some activate membrane-bound enzymes => increase “2nd messengers” F16-20

– 2nd messenger = cAMP F16-24• adenyl cyclase => ATP to cAMP

cAMP phosphodiesterase => cAMP to ATPcAMP dependent protein kinase activation by CampcAMP => both rapid and slow responses F16-23

– 2nd messengers = IP3 & DAGphospholipase c => IP3 & DAG F16-25

IP3 => opens ER Ca+2 channels . >>>> cytoplasmic Ca+2.> free Ca+2 => many effects

DAG (w free Ca+2) => activated PKC to inner face of membraneactivated PKC => many effects

– 2nd messenger = Ca+2free Ca+2 => many effect via Ca+2 binding proteins

e.g. calmodulin & calmodulin dependent protein kinases


Some regulate ion channels


Some activate membrane-bound enzymes => increase “2nd

messengers”


2nd messenger =

cAMP


2nd messenger =

cAMP


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2nd messengers =

IP3 & DAG


Cell Signaling Enzyme Linked Receptors

• Transmembrane proteins• cytoplasmic domain is enzyme or interacts w

enzyme• When ligand is soluble signaling protein, action

usually gene regulation – slow

• Receptor Tyrosine Kinases (= RTK)– Ligand binding => – dimerization of RTK subunits => – activate kinase activity => – binding of intracellular signaling proteins F16-30

– protein phosphatases remove P from RTK

• Intracellular signaling proteins include– a phospholipase that, like PLC, activates IP3 pathway– a PI 3-kinase that PO4s membrane IPLs, then bind other

signaling proteins– Ras: important in loss of control of cell division, & thus in

cancer



• All RTKs Activate Ras – Ras = One of lg family of monomeric GTP Binding Proteins

F16-31

• NOT trimeric like G protein• resembles a subunit of trimeric G proteins• Activated by binding GTP• Inactivated by hydrolysis of its own bound GTP

• Activated Ras activates MAP kinase phosphorylation cascade F16-32

• Effect of inactivating Ras => cell ignores signals to divide• Effects of permanent activation of Ras => cell acts as if

constantly receiving mitogens• Mutant Ras in cancer cells (~30% of all human cancers have

mutant) => constantly “on”


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16_32_MAP-kinase.jpg


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• Some activate fast track to the nucleus– Cytokines & a few hormones – JAK-STAT Pathway

• Receptor kinase activation => activation & translocation to nucleus of latent gene regulatory proteins held at plasma membrane F16-36

– SMAD PathwayF16-37

• RTKs of the TGF-b superfamily– important in animal development– Auto phosphorylation => recruits & activates a SMAD,

which releases, binds a different SMAD, move to nucleus & takes part in regulating gene activity


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Cell Signaling• SIGNALING PATHWAYS CAN BE HIGHLY INTERCONNECTED

F16-38

• (like nerve networks in brain or microprocessors in a computer)

• “... a major challenge to figure out how cell communication pieces fit togetherto allow cells to integrate environmental signals and to respond appropriately”


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Copyright © 2005 Pearson Prentice Hall, Inc