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Cell Signaling • – General Principles of Cell Signaling signaling cell => signaling molecule

Cell Signaling • – General Principles of Cell Signaling signaling cell => signaling molecule binds to receptor molecule on target cell Signaling Distances: => Four Types of Signaling • • Endocrine Paracrine Neuronal Contact Dependent • • T 16 -1 testosterone, TGF-b, acetylcholine, Delta Copyright © 2005 Pearson Prentice Hall, Inc. F. 16 -3

Cell Signaling • Receptor: – Each Target Cell Responds to Limited Set of Signals

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 • F 16 -5 A & C or F 16 -5 B & C Copyright © 2005 Pearson Prentice Hall, Inc.

 • Intracellular Cell Signaling Pathways: – Same receptor molecule can interact w/many intracellular

• Intracellular Cell Signaling Pathways: – Same receptor molecule can interact w/many intracellular relay systems so same signal & same receptor => different effects in different cells F 16 -5 A & B – Same relay system many act on many different intracellular targets F 16 -7 Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling • Target Cell Action: Depends upon ---- F 16 -6 – Signals

Cell Signaling • Target Cell Action: Depends upon ---- F 16 -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 F 16 -8 • Any target cell type at any one time has only a subset of all possible – Receptors, – Intracellular Relay Systems, – Intracellular Targets Copyright © 2005 Pearson Prentice Hall, Inc.

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16_08_cascades. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling • Signaling Cascades: Critical Functions • pp. 539 & 540 • (be

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 F 16 -29 • Distribute signal to >1 process simultaneously • Modulate signal to fit other internal & external conditions Copyright © 2005 Pearson Prentice Hall, Inc.

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16_29_amplifies_light. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling • Extracellular Signaling Molecules: • Two Types of Extracellular Signaling Molecules •

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 F 16 -10 vascular endothelial cells release NO activates guanyl cyclase in smooth muscle => relaxation => vasodilation guanyl cyclase: GTP = c. GMP nitroglycerine, erection, Viagra (blocks c. GMP reakdown) – Steroid Hormones Copyright © 2005 Pearson Prentice Hall, Inc. F 16 -11 & 12

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

Cell Signaling • Ligand for Cell Surface Receptor • (hydrophilic: don’t cross plasma membrane) F 16 -1 – Ion-Channel-Linked Receptors F 16 -14 A • convert chemical to electrical signals – G-protein-linked Receptors F 16 -14 B, & F 16 -17 • ligand binding => G-Protein activation by exchange bound GDP for GTP • Common structure = 7 -pass membrane protein – Enzyme-Linked Receptors Copyright © 2005 Pearson Prentice Hall, Inc. F 16 -16 F 16 -14 C

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16_13_receptor_protein. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling • Intracellular Signaling Molecules – Many are Molecular Switches – switched on

Cell Signaling • Intracellular Signaling Molecules – Many are Molecular Switches – switched on by signaling molecule, must also be turned off • Most common switching mechanisms T 16 -2 nicotine, morphine & heroin – phosphorylation F 16 -15 A – signal activated kinase; – dephosphorylation – phosphatase – GTP binding proteins: – GDP bound = inactive, – GTP bound = active Copyright © 2005 Pearson Prentice Hall, Inc. F 16 -15 B

Cell Signaling G-Protein Linked Receptors • • • Largest family of cell-surface receptors –

Cell Signaling G-Protein Linked Receptors • • • Largest family of cell-surface receptors – 100 s of members 7 -pass Transmembrane Proteins F 16 -16 Ligand binding Activates G-Protein subunits F 16 -17 Inactivated by hydrolysis of its own bound GTP F 16 -18 cholera toxin prevents this; G protein stays on => water & ion loss Copyright © 2005 Pearson Prentice Hall, Inc.

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16_18_Gprot_subunit. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling G-Protein Linked Receptors • Action mechanisms – Some regulate ion channels F

Cell Signaling G-Protein Linked Receptors • Action mechanisms – Some regulate ion channels F 16 -19 – 2 nd messenger = c. AMP F 16 -24 • Some activate membrane-bound enzymes => increase “ 2 nd messengers” F 16 -20 • adenyl cyclase => ATP to c. AMP phosphodiesterase => c. AMP to ATP c. AMP dependent protein kinase activation by Camp c. AMP => both rapid and slow responses – 2 nd messengers = IP 3 & DAG phospholipase c => IP 3 & DAG IP 3 => opens ER Ca+2 channels. >>>> cytoplasmic Ca+2. > free Ca+2 => many effects DAG (w free Ca+2) => activated PKC to inner face of membrane activated PKC => many effects – 2 nd messenger = Ca+2 free Ca+2 => many effect via Ca+2 binding proteins e. g. calmodulin & calmodulin dependent protein kinases Copyright © 2005 Pearson Prentice Hall, Inc. F 16 -23 F 16 -25

Some regulate ion channels Copyright © 2005 Pearson Prentice Hall, Inc.

Some regulate ion channels Copyright © 2005 Pearson Prentice Hall, Inc.

Some activate membrane-bound enzymes => increase “ 2 nd messengers” Copyright © 2005 Pearson

Some activate membrane-bound enzymes => increase “ 2 nd messengers” Copyright © 2005 Pearson Prentice Hall, Inc.

2 nd messenger = c. AMP Copyright © 2005 Pearson Prentice Hall, Inc.

2 nd messenger = c. AMP Copyright © 2005 Pearson Prentice Hall, Inc.

2 nd messenger = c. AMP Copyright © 2005 Pearson Prentice Hall, Inc.

2 nd messenger = c. AMP Copyright © 2005 Pearson Prentice Hall, Inc.

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16_23_slowly_rapidly. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

2 nd messengers = IP 3 & DAG Copyright © 2005 Pearson Prentice Hall,

2 nd messengers = IP 3 & DAG Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling Enzyme Linked Receptors • • • Transmembrane proteins cytoplasmic domain is enzyme

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 protein phosphatases remove P from RTK Intracellular signaling proteins include F 16 -30 a phospholipase that, like PLC, activates IP 3 pathway a PI 3 -kinase that PO 4 s membrane IPLs, then bind other signaling proteins Ras: important in loss of control of cell division, & thus in cancer Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling Enzyme Linked Receptors • All RTKs Activate Ras – Ras = One

Cell Signaling Enzyme Linked Receptors • All RTKs Activate Ras – Ras = One of lg family of monomeric GTP Binding Proteins • • F 16 -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 F 16 -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” Copyright © 2005 Pearson Prentice Hall, Inc.

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16_34_Ras_transmits. jpg Copyright © 2005 Pearson Prentice Hall, Inc.

Cell Signaling Enzyme Linked Receptors • Some activate fast track to the nucleus –

Cell Signaling Enzyme Linked Receptors • 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 F 16 -36 – SMAD Pathway • RTKs of the TGF-b superfamily F 16 -37 – 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 Copyright © 2005 Pearson Prentice Hall, Inc.

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 • SIGNALING PATHWAYS CAN BE HIGHLY INTERCONNECTED Cell Signaling F 16 -38 •

• SIGNALING PATHWAYS CAN BE HIGHLY INTERCONNECTED Cell Signaling F 16 -38 • (like nerve networks in brain or microprocessors in a computer) • “. . . a major challenge to figure out how cell communication pieces fit together to allow cells to integrate environmental signals and to respond appropriately” Copyright © 2005 Pearson Prentice Hall, Inc.

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