Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.
The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.
Wang
H G
HG
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pathan
N
N
Ethell
I M
IM
Krajewski
S
S
Yamaguchi
Y
Y
Shibasaki
F
F
McKeon
F
F
Bobo
T
T
Franke
T F
TF
Reed
J C
JC
D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D048948:14-3-3 Proteins; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C494821:Bad protein, rat; C494813:Bcl2l1 protein, rat; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D018698:Glutamic Acid; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D019703:Calcineurin; D002118:Calcium