Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta.
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.
Beffert
Uwe
U
Department of Molecular Genetics, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Morfini
Gerardo
G
Bock
Hans H
HH
Reyna
Huichuan
H
Brady
Scott T
ST
Herz
Joachim
J
D000818:Animals; D001921:Brain / Q000196:embryology / Q000201:enzymology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D000091042:Reelin Protein; D012694:Serine / Q000378:metabolism; D012697:Serine Endopeptidases; D015398:Signal Transduction; D013347:Subcellular Fractions; D013912:Threonine / Q000378:metabolism; D014162:Transfection
D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D000091042:Reelin Protein; D012694:Serine; D012697:Serine Endopeptidases; D013912:Threonine; C000717129:Reln protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; C000717127:RELN protein, human; C000717128:Reln protein, mouse