Xm. Zhou et al., Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser(155), J BIOL CHEM, 275(32), 2000, pp. 25046-25051
The Bcl-2 family protein BAD promotes apoptosis by binding through its BH3
domain to Bcl-x(L) and related cell death suppressors. When BAD is phosphor
ylated on either Ser(12) or Ser(136), it forms a complex with 14-3-3 in the
cytosol and no longer interacts with Bcl-x(L) at the mitodhondria. Here we
show that phosphorylation of a distinct site Ser(155), which is at the cen
ter of the BAD BH3 domain, directly suppressed the pro-apoptotic function o
f BAD by eliminating its affinity for Bcl-x(L) Protein kinase A functioned
as a BAD Ser(155) kinase bath fn vitro and in cells. BAD Ser(155) was found
to be a major site of phosphorylation induced following stimulation by gro
wth factors and prevented by protein kinase A inhibitors but not by inhibit
ors of the phosphatidylinosital 3-kinase/Akt pathway, Growth factors inhibi
ted BAD-induced apoptosis in both a Ser(112)/Ser(136)- and a Ser(155)-depen
dent fashion. Thus, growth factors engage an anti-apoptotic signaling pathw
ay that inactivates BAD by direct modification of its BH3 cell death effect
or domain.