Phosphatidylinositol 3-Kinase Interacts with the Adaptor Protein Dab1 in Response to Reelin Signaling and Is Required for Normal Cortical Lamination

Reelin is a large secreted signaling protein that binds to two members of the low density lipoprotein receptor family, the apolipoprotein E receptor 2 and the very low density lipoprotein receptor, and regulates neuronal positioning during brain development. Reelin signaling requires activation of S...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-10, Vol.278 (40), p.38772-38779
Main Authors: Bock, Hans H., Jossin, Yves, Liu, Pingsheng, Förster, Eckart, May, Petra, Goffinet, André M., Herz, Joachim
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Apolipoproteins E - metabolism
beta-Cyclodextrins
Brain - embryology
Brain - metabolism
Catalysis
Cell Adhesion Molecules, Neuronal - chemistry
Cell Adhesion Molecules, Neuronal - metabolism
Cell Membrane - metabolism
Cell Movement
Cells, Cultured
Cholesterol - metabolism
Cyclodextrins - metabolism
Cytosol - metabolism
Enzyme Activation
Extracellular Matrix Proteins - chemistry
Extracellular Matrix Proteins - metabolism
Fungal Proteins - chemistry
Fungal Proteins - metabolism
Glycogen Synthase Kinase 3 - metabolism
Immunoblotting
Ligands
Molecular Sequence Data
Nerve Tissue Proteins
Neurons - metabolism
Phosphatidylinositol 3-Kinases - chemistry
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Precipitin Tests
Protein Binding
Protein Structure, Tertiary
Rats
Receptors, LDL - metabolism
Serine Endopeptidases
Signal Transduction
Subcellular Fractions - metabolism
Tyrosine - metabolism
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Summary:Reelin is a large secreted signaling protein that binds to two members of the low density lipoprotein receptor family, the apolipoprotein E receptor 2 and the very low density lipoprotein receptor, and regulates neuronal positioning during brain development. Reelin signaling requires activation of Src family kinases as well as tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). This results in activation of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and the inhibition of glycogen synthase kinase 3β, a protein that is implicated in the regulation of axonal transport. Here we demonstrate that PI3K activation by Reelin requires Src family kinase activity and depends on the Reelin-triggered interaction of Dab1 with the PI3K regulatory subunit p85α. Because the Dab1 phosphotyrosine binding domain can interact simultaneously with membrane lipids and with the intracellular domains of apolipoprotein E receptor 2 and very low density lipoprotein receptor, Dab1 is preferentially recruited to the neuronal plasma membrane, where it is phosphorylated. Efficient Dab1 phosphorylation and activation of the Reelin signaling cascade is impaired by cholesterol depletion of the plasma membrane. Using a neuronal migration assay, we also show that PI3K signaling is required for the formation of a normal cortical plate, a step that is dependent upon Reelin signaling.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M306416200