Abstract
Reelin is a large secreted protein that controls cortical layering by signaling through the very low density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1) and suppressing tau phosphorylation in vivo. Here we show that binding of Reelin to these receptors stimulates phosphatidylinositol 3-kinase, resulting in activation of protein kinase B and inhibition of glycogen synthase kinase 3beta. We present genetic evidence that this cascade is dependent on apolipoprotein E receptor 2, very low density lipoprotein receptor, and Dab1. Reelin-signaling components are enriched in axonal growth cones, where tyrosine phosphorylation of Dab1 is increased in response to Reelin. These findings suggest that Reelin-mediated phosphatidylinositol 3-kinase signaling in neuronal growth cones contributes to final neuron positioning in the mammalian brain by local modulation of protein kinase B and glycogen synthase kinase 3beta kinase activities.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Brain / embryology
-
Brain / enzymology
-
Cell Adhesion Molecules, Neuronal / metabolism*
-
Cell Line
-
Enzyme Inhibitors / pharmacology
-
Extracellular Matrix Proteins / metabolism*
-
Gene Expression Regulation, Enzymologic*
-
Glycogen Synthase Kinase 3 / metabolism*
-
Glycogen Synthase Kinase 3 beta
-
Homozygote
-
Humans
-
Immunoblotting
-
Immunohistochemistry
-
Mice
-
Mice, Inbred C57BL
-
Models, Biological
-
Nerve Tissue Proteins
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphorylation
-
Precipitin Tests
-
Protein Binding
-
Protein Serine-Threonine Kinases*
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-akt
-
Rats
-
Recombinant Proteins / metabolism
-
Reelin Protein
-
Serine / metabolism
-
Serine Endopeptidases
-
Signal Transduction*
-
Subcellular Fractions
-
Threonine / metabolism
-
Transfection
Substances
-
Cell Adhesion Molecules, Neuronal
-
Enzyme Inhibitors
-
Extracellular Matrix Proteins
-
Nerve Tissue Proteins
-
Proto-Oncogene Proteins
-
Recombinant Proteins
-
Reelin Protein
-
Reln protein, rat
-
Threonine
-
Serine
-
AKT1 protein, human
-
Akt1 protein, rat
-
GSK3B protein, human
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, mouse
-
Gsk3b protein, rat
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
Glycogen Synthase Kinase 3
-
RELN protein, human
-
Reln protein, mouse
-
Serine Endopeptidases