Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery.
A mechanism that triggers neuronal apoptosis has been characterized. We report that the cell cycle-regulated protein kinase Cdc2 is expressed in postmitotic granule neurons of the developing rat cerebellum and that Cdc2 mediates apoptosis of cerebellar granule neurons upon the suppression of neuronal activity. Cdc2 catalyzes the phosphorylation of the BH3-only protein BAD at a distinct site, serine 128, and thereby induces BAD-mediated apoptosis in primary neurons by opposing growth factor inhibition of the apoptotic effect of BAD. The phosphorylation of BAD serine 128 inhibits the interaction of growth factor-induced serine 136-phosphorylated BAD with 14-3-3 proteins. Our results suggest that a critical component of the cell cycle couples an apoptotic signal to the cell death machinery via a phosphorylation-dependent mechanism that may generally modulate protein-protein interactions.
Konishi
Yoshiyuki
Y
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Lehtinen
Maria
M
Donovan
Nicole
N
Bonni
Azad
A
D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000166:cytology; D010766:Phosphorylation; D011485:Protein Binding; D011817:Rabbits; D012694:Serine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051025:bcl-Associated Death Protein
D048948:14-3-3 Proteins; C494820:Bad protein, mouse; D002352:Carrier Proteins; D051025:bcl-Associated Death Protein; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D016203:CDC2 Protein Kinase