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Cell signaling
1.
Copyright © 2005
Pearson •http://aimediaserver.com/studiodaily/videoplayer/?src=harvard/harvard.swf&width=640&height=520
2.
Copyright © 2005
Pearson 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
3.
Copyright © 2005
Pearson 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 •
4.
Copyright © 2005
Pearson 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
5.
Copyright © 2005
Pearson 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
6.
Copyright © 2005
Pearson 16_06_extracellular_sig.jpg
7.
Copyright © 2005
Pearson 16_08_cascades.jpg
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Copyright © 2005
Pearson 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
9.
Copyright © 2005
Pearson 16_29_amplifies_light.jpg
10.
Copyright © 2005
Pearson 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 •
11.
Copyright © 2005
Pearson 16_09_molecules_bind.jpg
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Copyright © 2005
Pearson 16_10_Nitric_oxide.jpg
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Copyright © 2005
Pearson 16_11_phobic_hormone.jpg
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Pearson 16_12_cortisol.jpg
15.
Copyright © 2005
Pearson 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 Receptors F16-14C
16.
Copyright © 2005
Pearson 16_14_3_basic_classes.jpg
17.
Copyright © 2005
Pearson 16_13_receptor_protein.jpg
18.
Copyright © 2005
Pearson 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
19.
Copyright © 2005
Pearson Cell Signaling G-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
20.
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Pearson 16_18_Gprot_subunit.jpg
21.
Copyright © 2005
Pearson Cell Signaling G-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 ATP cAMP dependent protein kinase activation by Camp cAMP => both rapid and slow responses F16-23 – 2nd messengers = IP3 & DAG phospholipase 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 membrane activated PKC => many effects – 2nd messenger = Ca+2 free Ca+2 => many effect via Ca+2 binding proteins e.g. calmodulin & calmodulin dependent protein kinases
22.
Copyright © 2005
Pearson Some regulate ion channels
23.
Copyright © 2005
Pearson Some activate membrane-bound enzymes => increase “2nd messengers”
24.
Copyright © 2005
Pearson 2nd messenger = cAMP
25.
Copyright © 2005
Pearson 2nd messenger = cAMP
26.
Copyright © 2005
Pearson 16_23_slowly_rapidly.jpg
27.
Copyright © 2005
Pearson 2nd messengers = IP3 & DAG
28.
Copyright © 2005
Pearson 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
29.
Copyright © 2005
Pearson Cell Signaling Enzyme Linked Receptors • 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”
30.
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Pearson 16_31_active_Ras.jpg
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Pearson 16_32_MAP-kinase.jpg
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Pearson 16_34_Ras_transmits.jpg
33.
Copyright © 2005
Pearson 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 F16-36 – SMAD Pathway F16-37 • 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
34.
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Pearson 16_36_Cytokine_recpt.jpg
35.
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Pearson 16_37_TGF_B_receptor.jpg
36.
Copyright © 2005
Pearson 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 together to allow cells to integrate environmental signals and to respond appropriately”
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Pearson 16_38_Signal_pathways.jpg
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Pearson 16_39_integrate_signal.jpg
Editor's Notes
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16_06_extracellular_sig.jpg
16_08_cascades.jpg
16_29_amplifies_light.jpg
16_09_molecules_bind.jpg
16_10_Nitric_oxide.jpg
16_11_phobic_hormone.jpg
16_12_cortisol.jpg
16_14_3_basic_classes.jpg
16_13_receptor_protein.jpg
16_18_Gprot_subunit.jpg
16_19_open_K_chan.jpg
16_20_second_messeng.jpg
16_21_Cyclic_AMP.jpg
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16_23_slowly_rapidly.jpg
16_25_PhospholipaseC.jpg
16_31_active_Ras.jpg
16_32_MAP-kinase.jpg
16_34_Ras_transmits.jpg
16_36_Cytokine_recpt.jpg
16_37_TGF_B_receptor.jpg
16_38_Signal_pathways.jpg
16_39_integrate_signal.jpg
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