14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.
The Bcl-2 homology 3 (BH3) domain of prodeath Bcl-2 family members mediates their interaction with prosurvival Bcl-2 family members and promotes apoptosis. We report that survival factors trigger the phosphorylation of the proapoptotic Bcl-2 family member BAD at a site (Ser-155) within the BAD BH3 domain. When BAD is bound to prosurvival Bcl-2 family members, BAD Ser-155 phosphorylation requires the prior phosphorylation of Ser-136, which recruits 14-3-3 proteins that then function to increase the accessibility of Ser-155 to survival-promoting kinases. Ser-155 phosphorylation disrupts the binding of BAD to prosurvival Bcl-2 proteins and thereby promotes cell survival. These findings define a mechanism by which survival signals inactivate a proapoptotic Bcl-2 family member, and suggest a role for 14-3-3 proteins as cofactors that regulate sequential protein phosphorylation events.
Datta
S R
SR
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Katsov
A
A
Hu
L
L
Petros
A
A
Fesik
S W
SW
Yaffe
M B
MB
Greenberg
M E
ME
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; 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; D002352:Carrier Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases