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Phosphorylation of BCL‐2 regulates ER Ca 2+ homeostasis and apoptosis
Author(s) -
Bassik Michael C,
Scorrano Luca,
Oakes Scott A,
Pozzan Tullio,
Korsmeyer Stanley J
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600104
Subject(s) - phosphorylation , endoplasmic reticulum , biology , apoptosis , microbiology and biotechnology , bcl 2 family , programmed cell death , unfolded protein response , biochemistry
Phosphorylation of BCL‐2 within an unstructured loop inhibits its antiapoptotic effect. We found that phosphorylated BCL‐2 predominantly localized to the endoplasmic reticulum (ER) and tested whether phosphorylation would control its activity at this organelle, where Ca 2+ dynamics serve as a critical control point for apoptosis. Phosphorylation greatly inhibits the ability of BCL‐2 to lower [Ca 2+ ] er and protect against Ca 2+ ‐dependent death stimuli. Cells expressing nonphosphorylatable BCL‐2 AAA exhibited increased leak of Ca 2+ from the ER and further diminished steady‐state [Ca 2+ ] er stores when compared to cells expressing BCL‐2 wt . Consequently, when BCL‐2 is phosphorylated, Ca 2+ discharge from the ER is increased, with a secondary increase in mitochondrial Ca 2+ uptake. We also demonstrate that phosphorylation of BCL‐2 inhibits its binding to proapoptotic family members. This inhibitory mechanism manifested at the ER, where phosphorylated BCL‐2 was unable to bind proapoptotic members. [Ca 2+ ] er proved coordinate with the capacity of BCL‐2 to bind proapoptotic BH3‐only members, further integrating the apoptotic pathway and Ca 2+ modulation. Unexpectedly, the regulation of ER Ca 2+ dynamics is a principal avenue whereby BCL‐2 phosphorylation alters susceptibility to apoptosis.