Reelin signals survival through Src-family kinases that inactivate BAD activity.
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.
Ohkubo
Nobutaka
N
Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, Japan. nobu@m.ehime-u.ac.jp
Vitek
Michael P
MP
Morishima
Atsuyuki
A
Suzuki
Yoji
Y
Miki
Tetsuro
T
Maeda
Nobuji
N
Mitsuda
Noriaki
N
D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000091042:Reelin Protein; D051025:bcl-Associated Death Protein; D014212:Tretinoin; D019061:src-Family Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D048490:raf Kinases; D038362:Glycogen Synthase Kinase 3; C000717127:RELN protein, human; D012697:Serine Endopeptidases