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Molecular Biology of THE CELL 4 th edition Chapter 15 Cell Communication
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Single cell Multicellular organism
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GENERAL PRINCIPLES OF CELL COMMUNICATION Extracellular signal molecules bind to specific receptors
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Extracellular signal molecules can act over either short or long distance
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Autocrine signaling can coordinate decision by groups of identical cells “Community effect” in early development In tumor biology---cancer cells stimulate their own proliferation
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Gap junctions allow signaling information to be shared by neighboring cells Ca 2+, cAMP etc. but not for proteins or nucleic acids Intracellular electrodes, small water-soluble dyes Connexin 43 deficiency --- abnormal heart development
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Each cell is programmed to respond to specific combinations of extracellular signal molecules
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Different cells can respond differently to the same extracellular signal molecules
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The concentration of a molecule can be adjusted quickly only if the lifetime of the molecule is short
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Nitric oxide gas signals by binding directly to an enzyme inside the target cell Nitroglycerine --- angina Viagra --- PDE inhibitor CO
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Nuclear receptors are ligand-activated gene regulatory proteins
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Ligand-binding domain
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The three largest classes of cell-surface receptor proteins are ion-channel-linked, G-proteins-linked, and enzyme-linked receptors
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Most activated cell-surface receptors relay signals via small molecules and a network of intracellular signaling proteins SCIENCE 281, 1671-1674 (1998) A Mammalian Scaffold Complex That Selectively Mediates MAP Kinase Activation (JNK interacting protein-1. JIP-1) Alan J. Whitmarsh, Julie Cavanagh, Cathy Tournier, Jun Yasuda, Roger J. Davis*
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Some intracellular signaling proteins act as molecular switches ~2% of human genes (576 kinases in human genome) Monomeric GTPase Trimeric GTPase
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Signal integration by protein phosphorylation
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Intracellular signaling complexes enhance the speed, efficiency, and specificity of the response
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Complex forms transiently
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Interactions between intracellular signaling proteins are mediated by modular binding domains
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SCIENCE 278, 2075-2080 (1997) Signaling Through Scaffold, Anchoring, and Adaptor Proteins Tony Pawson and John D. Scott
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PDZ Domain Domain binding and function: PDZ domains bind to the C-terminal 4 – 5 residues of their target proteins, frequently transmembrane receptors or ion channels. These interactions can be of high affinity (nM K d ). The consensus binding sequence contains a hydrophobic residue, commonly Val or Ile, at the very C-terminus. Residues at the – 2 and – 3 positions are important in determining specificity. PDZ domains can also heterodimerize with PDZ domains of different proteins, potentially regulating intracellular signaling. In addition to engaging in protein- protein interactions, several PDZ domains including those of syntenin, CASK, Tiam1 and FAP are capable of binding to the phosphoinositide PIP 2. PIP 2 -PDZ domain binding is thought to control the association of PDZ domain-containing proteins with the plasma membrane. Structure Reference: Doyle, D.A. et al. (1996) Cell 85(7), 1067 – 1076. The third PDZ domain from PSD-95. www.cellsignal.com
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Cells can respond abruptly to a gradually increasing concentration of an extracellular signal Chicken oviduct cells Stimulated by estradiol effector/target : 1~16 maximal activation
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One type of signaling mechanism expected to show a steep threshold-like response
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A cell can remember the effect of some signals Signals trigger muscle cell determination
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Cells can adjust their sensitivity to a signal
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SIGNALING THROUGH G-PROTEIN-LINKED CELL-SURFACE RECEPTORS 1. The largest family of cell-surface receptors 2. 5% of the C. elegans genes 3. Signal molecules: hormones, neurotransmitters and local medicators 4. Rhodopsin-light receptor 5. Genome sequencing --- vast numbers of new family members 6. Major targets for drug discovery
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Trimeric G proteins disassemble to relay signals from G-protein-linked receptors Transducin-G protein in visual transduction
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The disassembly of a activated G-protein into two signaling components
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The switching off of the G-protein subunit by the hydrolysis of its bound GTP RGS proteins --- regulators of G protein signaling, act as subunit-specific GTPase activating proteins (GAPs) ~25 RGS proteins in the human genome
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Some G-proteins signal by regulating the production of cyclic AMP Nerve cell culture, preloaded with a fluorescent protein that changes its fluorescence when it binds to cAMP. >10 -6 M~5 X 10 -8 M (Science 260:222-226, 1993)
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cAMP-dependent protein kinase (PKA) mediate most of the effects of cyclic AMP Role of cAMP, PKA in glycogen metabolism
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How gene transcription is activated by a rise in cAMP concentration (CRE, cAMP response element) Role of protein phosphatases?
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Some G-proteins activate the inositol phospholipid signaling pathway by activating phospholipase C- (<1% of total phospholipids)
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The two branches of the inositol phospholipid pathway
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Ca 2+ functions as a ubiquitous intracellular messenger Ca 2+ signaling in fertilization of starfish, detected by Ca 2+ -sensitive fluorescence dye
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The main ways eucaryotic cells maintain a very low concentration of free Ca 2+ in their cytosol
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The frequency of Ca 2+ oscillations influences a cell’s response In a liver cell
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Ca 2+ /calmodulin-dependent protein kinases (CaM-kinases) mediate many of the actions of Ca 2+ in animal cells The structure of Ca 2+ /calmodulin A peptide derived from CaM-Kinase II
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The activation of CaM-kinases II ~2% of total mass in some brain regions, especially in synapses It can function as a molecular memory device --- (1)Learning defect (where things are in space) in mutant mice that lack the brain-specific subunit of CaM-kinase II (2) Same defect also observed in mutant mice that have their CaM-kinase II mutated at the autophosphorylation site
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CaM-kinases II as a frequency decoder of Ca 2+ oscillations CaM-kinase II is immobilized on a solid surface +a brain protein phosphatase +repetitive pulse of Ca 2+ /calmodulin at different frequency Kinase activity assay [Science. 1998 Jan 9;279(5348):227-30.]
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Smell and vision depend on G-protein-linked receptors that regulate cyclic-nucleotide-gated ion channels
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Cyclic GMP A rod photoreceptor cell
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The response of a rod photoreceptor cell to light
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Extracellular signals are greatly amplified by the use of small intracellular mediators and enzymatic cascades Amplification in the light-induced catalytic cascade in vertebrate rods
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G-protein-linked receptors desensitization depends on receptor phosphorylation
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SIGNALING THROUGH ENZYME-LINKED CELL-SURFACE RECEPTORS Six classes: 1. Receptor tyrosine kinases 2. Tyrosine kinase-associated receptors 3. Receptorlike tyrosine phosphatases 4. Receptor serine/threonine kinases 5. Receptor guanylyl cyclases 6. Histidine-kinase-associated receptors
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Activated tyrosine kinases phosphorylate themselves angiogenesis cell/axon migration
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Three ways in which signaling proteins can cross-link receptor chains Monomeric vs. dimeric ligand
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Inhibition of signaling through normal receptor tyrosine kinases by an excess of mutant receptors As a tool for determining normal function of receptor
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Phosphorylated tyrosine serves as docking sites for proteins with SH2 domains
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The binding of SH2-containing intracellular signaling proteins to an activated PDGF receptor determine the binding specificity
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Ras is activated by a guanine nucleotide exchange factor GEF: guanine nucleotide exchange factor GAP: GTPase-activating protein In cells [GTP] > [GDP] ~10 fold
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The activation of Ras by an activated receptor tyrosine kinase
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The MAP-kinase serine/threonine phosphorylation pathway activated by Ras
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The organization of MAP-kinase pathway by scaffold proteins in budding yeast
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PI 3-kinase produces inositol phospholipid docking sites in the plasma membrane Cell division vs. cell growth PI 3 kinase is one of the major cell growth signaling transduces
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The recruitment of signaling proteins with PH domains to the plasma membrane during B cell activation SH2 domain Mutation of BTK leads to severely deficiency in Ab production
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The PI 3-kinase/protein kinase B signaling pathway can stimulate cells to survive and grow
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Brief summarization
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Signal proteins of the TGF- superfamily act through receptor serine/threonine kinases and Smads
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Kinase catalytic domain ~250 amino acids
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SIGNALING PATHWAY THAT DEPENDS ON REGULATED PROTEOLYSIS 1.Notch 2.Wnt 3.Hedgehog 4.NF-kB
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The receptor protein Notch is activated by cleavage In Drosophila, mutation in Delta leads to produce a huge excess of neurons at the expense of epidermal cells
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The processing and activation of Notch by proteolytic cleavage Inhibit neural differentiation
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Wnt proteins bind to Frizzled receptors and inhibit the degradation of -catenin (c-Myc protein)(APC, adenomatous polyposis coli, a tumor suppressor )
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Multiple stressful and proinflammatory stimuli act through an NF-B-dependent signaling pathway inflammation development cancer
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