Ca2+-Induced Apoptosis Through Calcineurin Dephosphorylation of BAD

HG Wang, N Pathan, IM Ethell, S Krajewski… - Science, 1999 - science.org
HG Wang, N Pathan, IM Ethell, S Krajewski, Y Yamaguchi, F Shibasaki, F McKeon, T Bobo…
Science, 1999science.org
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 …
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.
AAAS