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MF_9_PIPs_11 - Summary of Phosphoinositide Signaling...

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Unformatted text preview: Summary of Phosphoinositide Signaling Activate Phospholipase C (PLC β or γ ) 3 IP releases calcium DAG plus calcium activates PKC Promotes cell growth Activate Phospholipase A2 (PLA2) arachidonic acid: prostaglandins, inflammation Activate PhosphatidylInositol-3 Kinase (PI-3K) Pleckstrin Homology (PH) domain proteins recruited Protein Kinase B (PKB; Akt) Growth Growth mTOR Differentiation Block programmed cell death (apoptosis) BAD Phospholipases Phospholipase Cleavage Sites Sites Phospholipase D Phospholipase C Phospholipase A1 Phospholipase A2 Phosphatidyl Inositol Phosphatidyl Inositol Structure PI PIP2 PIP PLC Phospholipase C (PLC) Cleaves PIP2 to Diacylglycerol (DAG) + Inositol triphosphate (IP3) PLC- β GPCRs Activate PLC- β PLC - γ Activation of PLC- γ in RTK Pathway Ca++ Release Channel Calcium Release Channel in ER Muscle Cell Channel is Ryanodine Receptor IP3 insensitive channel Physical coupling of plasma membrane and ER at T-tubule Homotetramer Non-Muscle Channel is IP3 Sensitive Non-Muscle cells have no T-tubule invaginations Use IP3 as secondary messenger to propagate signal over distance Why is it advantageous for cells to use IP3 to regulate calcium? IP3 has longer path in cytosol than calcium In extract, D for calcium is low due to sequestration by binding proteins Provides explanation for second messenger IP3 Science 258, 1812-1815 X = (2Dt) 1/2 (2Dt) 1/2 Range for calcium estimated to be 0.1 to 5 µm Range for IP3 estimated to be 25 µm. Calmodulin Targets of Calcium in Cytoplasm: Calmodulin Transient Increase in Ca++ Calcium Pump Removes Ca++ Proteins Bind Ca++ Recognize Ca++ vs Mg++ Protein Kinase C Calpain- protease Calcineurin- phosphatase Calcineurinalpha-actinin- binds actin Troponin C Calmodulin Dumbbell structure 4 EF Hands Bind calcium Calmodulin folds around target Hydrophobic interaction CAM Kinase II (See Fig. 15-44) Myosin Light Chain Kinase PKC Protein Kinase C Tumor Promotor Tumor Phorbol Esters Activate Lipids contribute to activation (diacylglyerol; phosphatidyl Lipids serine) serine) Isoforms differ in structure and regulation Synthesized in inactivative state Some forms activated by calcium; Some forms calcium independent Multiple sites of phosphorylation including autophosphorylation PKC anchoring proteins control localization Substrates Sodium/Proton Antiport 5 P’tase (Cleaves phosphate from carbon 5 of IP3 to produce IP2). Stops calcium signaling PI-3K Activation Activation of PI-3 Kinase in RTK Pathway PI-3 Kinase activation is required for growth factors to promote cell divisio PI3K activation can also be promoted by ras. PI-3K PI-3 Kinase A kinase that phosphorylates a phospholipid on carbon 3 of the inositol ring. PI-3K/PTEN PI-3 Kinase PI-3 Kinase promotes cell division. 3-Phosphatase turns off the Signal (PTEN) PTEN is a tumor suppressor PKB Activation of Protein Kinase B (Akt) Requires Binding of the PH Domain to 3phosphoinositides, and Phosphorylation of PKB by PDK1 ote: PDK1 is a protein kinase that has its own PH domain. PKB Regulates Apoptosis PI-3K Pathway Promotes Growth/Survival; Growth/Survival; Protein Kinase B Phosphorylates Protein Bad to Block Programmed Cell Bad Death (Apoptosis) Death PI-3K mTOR PI-3K Pathway Promotes Growth/Survival; PI-3K Protein Kinase B Activates mTOR to Promote Protein mTOR Cell Growth Cell (mTOR is mammalian Target Of Rapamycin; protein kinase) (mTOR ammalian arget Grpwth factors bind RTKs and stimulate protein synthesis. Activate PI-3K Activate Akt Inactivate Tsc-2 Tsc2 is a GAP That inactives Rheb. Rheb-GTP actives mTOR. mTOR promotes cell growth by stimulating protein synthesis, ribosome synthesis,and nutrient uptake, Summarize PI Signaling Summary of Phosphoinositide Signaling Activate Phospholipase C (PLC β or γ ) 3 IP releases calcium DAG plus calcium activates PKC Promotes cell growth Activate Phospholipase A2 (PLA2) arachidonic acid: prostaglandins, inflammation Activate PhosphatidylInositol-3 Kinase (PI-3K) Pleckstrin Homology (PH) domain proteins recruited Protein Kinase B (PKB; Akt) Growth Growth mTOR Differentiation Block programmed cell death (apoptosis) Summarize Signaling Pathways BAD Connections Between Signaling Pathways ...
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