Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155.
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 phosphorylated on either Ser(112) or Ser(136), it forms a complex with 14-3-3 in the cytosol and no longer interacts with Bcl-x(L) at the mitochondria. Here we show that phosphorylation of a distinct site Ser(155), which is at the center of the BAD BH3 domain, directly suppressed the pro-apoptotic function of BAD by eliminating its affinity for Bcl-x(L). Protein kinase A functioned as a BAD Ser(155) kinase both in vitro and in cells. BAD Ser(155) was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors but not by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Growth factors inhibited BAD-induced apoptosis in both a Ser(112)/Ser(136)- and a Ser(155)-dependent fashion. Thus, growth factors engage an anti-apoptotic signaling pathway that inactivates BAD by direct modification of its BH3 cell death effector domain.
Zhou
X M
XM
Apoptosis Technology, Inc., Cambridge, Massachusetts 02139, USA. xiao-mai.zhou@immunogen.com
Liu
Y
Y
Payne
G
G
Lutz
R J
RJ
Chittenden
T
T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012694:Serine; D014162:Transfection; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
C494819:BAD protein, human; C494811:BCL2L1 protein, human; C494821:Bad protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D012694:Serine; D004815:Epidermal Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases