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Lipid signaling

Lipid signaling. Lipid structures Phospholipids Sphingolipids Lipid modifying enzymes Second messenger effectors DAG, PA IP3 Arachidonic acid. Phospholipids. Glycerol Backbone 2 hydrophobic acyl tails Large polar “head group” Cholesterol. Hydrophobic core. Polar transition.

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Lipid signaling

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  1. Lipid signaling • Lipid structures • Phospholipids • Sphingolipids • Lipid modifying enzymes • Second messenger effectors • DAG, PA • IP3 • Arachidonic acid

  2. Phospholipids • Glycerol Backbone • 2 hydrophobic acyl tails • Large polar “head group” • Cholesterol Hydrophobic core Polar transition Solvent cloud

  3. Sphingolipids • Amine backbone with integral acyl • Polar headgroup • One extra fatty acid tail, usually saturated

  4. Lipid modifiers • Phospholipids • PLA • PLC • PLD • Sphingolipids • Ceramidase • Sphingomyelinase • No PLD equivalent

  5. Phospholipase C • PI-directed lipases • Dependent on membrane association • Frequently Gaq; sometimes phosphorylation • PLC  • PIP2DAG + IP3 • Ca2+ • PKC • Reduces PIP2 • Block synthesis of PIP3 • Block PI3-K

  6. PLC • Membrane localization • G binding (50 nM) • Pleckstrin homology (PI-3P binding) • Frequently nuclear, stimulating DNA synth • This mode is ERK 1/2, not Gq, dependent • Deactivation • PLC:Gq ATPase activity ~50x native Gq • RGS PLCb C-terminal dimer binds 2 Gaq Singer et al., 2001

  7. PLC • Membrane localization • SH2 domain • PI(3,4,5)P3 • Activated by RTK mediated phosphorylation • PI-3K facilitated recruitment antagonizes PI-3K

  8. PLC, PLC • Poorly characterized • Delta • Highly Ca2+ dependent • PI (3,4,5) P3/PI (4,5) P2 • Gh (thromboxane, oxytocin) • Epsilon • Ras binding • No PH domain

  9. IP3 • Endoplasmic reticulum IP3 channel • IP3 gated • Ca2+ activated

  10. Protein Kinase C • S/T kinases regulated by membrane association (and sometimes Ca2+) • Conventional () • Ca2+ • DAG/PMA • Novel () • DAG • Unsaturated fatty acid • Atypical () • PS/PI/unsaturated fatty acid

  11. cPKC • Membrane targeted by DAG • Phosphorylation dependent • Ca2+ enhanced, PS • Phosphorylation • Thr497/500 • Autophosphorylation • RTK • Inhibition • Sphingosine

  12. Liu &Heckman 1998

  13. Localization • Isoform specific subcellular localization • Sensory axon terminals • Post-synaptic dendrites • Nuclear membrane • RACK • Receptor for activated C-Kinase • AKAP

  14. Effects • Response • Growth • Apoptosis • Motility • Substrates • Histone 3 • Myelin basic protein • Nuclear lamins • PLD

  15. Deactivation • Proteolytic cleavage • Separation from regulatory domain • Degradation of function • Phorbol ester mediated downregulation

  16. PI-3 kinase • Phosphorylates 3’ C of PI • PIP2PIP3 • p85 catalytic subunit, p110 regulatory subunit • RTKPI3KaktmTORprotein synthesis • RTKPI3Kakt--|FOXOapoptosis

  17. Phospholipase D • Cleaves PC to Phosphatidic acid+choline • PA • Multiple activation factors • cPKC • ADP ribosylation factors (ARF) • Gangliosides GM1 & GM2 • RhoA

  18. Phosphatidic Acid • Convert to DAG, secondary PKC activation • Cofactor for PI-4P 5-kinase • PIP2 synthesis • Raf/MAPK activation • mTOR • Membrane biophysics • Negative charge, calcium attactor, pH drop • Budding • Vesicular transport

  19. Phospholipase A2 • Cleaves sn-2 acyl chain from phospholipid • Calcium dependent cPLA2 • Specific for Arachidonic acid • Calcium independent iPLA2 • Secreted sPLA2 • Not acyl chain specific • Membrane degradation

  20. PLA2 • Arachidonic acid • Cyclooxygenase (COX) substrate • Prostaglandins, thromboxanes, prostacyclins • Paracrine factors • Pro/anti-inflammatory • Vasoactive • Phospholipid degradation • Venoms • Anti-coagulent • Atherosclerotic

  21. Legend for following slide Typical membrane content 20% PE Primary phospholipid Enzyme which generates PLC DAG Second messenger PKC Active effector

  22. Phospholipid metabolism Inositol CDP-DAG CDP-choline 20% PLA2 60% IP PI PE PC LysoPC 8% PEMT PI-4K PSD 1% PLD PS IP2 PIP 0.2% Choline PI-5K PKC 0.2% PLC DAG kinase PLC IP3 PIP2 DAG PA PA phosphatase Ca2+ PI3K PTEN Raf kinase mTOR DAG lipase MAG IP4 PIP3 PDK/mTOR

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