Abstract
Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3 K)/Akt pathway. When PI3 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Adhesion Molecules, Neuronal / antagonists & inhibitors
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Cell Adhesion Molecules, Neuronal / physiology*
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Cell Line
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Cell Survival / physiology
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Extracellular Matrix Proteins / antagonists & inhibitors
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Extracellular Matrix Proteins / physiology*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HeLa Cells
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Humans
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Mutation
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / physiology*
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Neurons / physiology*
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Oncogene Protein v-akt / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Reelin Protein
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Serine Endopeptidases / physiology*
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Signal Transduction / physiology*
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Stem Cells / physiology
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Transfection
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Tretinoin / pharmacology
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bcl-Associated Death Protein / genetics
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bcl-Associated Death Protein / physiology*
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raf Kinases / metabolism
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src-Family Kinases / physiology*
Substances
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Cell Adhesion Molecules, Neuronal
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Extracellular Matrix Proteins
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Nerve Tissue Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Reelin Protein
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bcl-Associated Death Protein
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Tretinoin
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src-Family Kinases
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Glycogen Synthase Kinase 3 beta
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Oncogene Protein v-akt
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raf Kinases
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Glycogen Synthase Kinase 3
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RELN protein, human
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Serine Endopeptidases