Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
Extracellular survival factors alter a cell's susceptibility to apoptosis, often through posttranslational mechanisms. However, no consistent relationship has been established between such survival signals and the BCL-2 family, where the balance of death agonists versus antagonists determines susceptibility. One distant member, BAD, heterodimerizes with BCL-X(L) or BCL-2, neutralizing their protective effect and promoting cell death. In the presence of survival factor IL-3, cells phosphorylated BAD on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated BAD heterodimerized with BCL-X(L) at membrane sites to promote cell death. Phosphorylated BAD was sequestered in the cytosol bound to 14-3-3. Substitution of serine phosphorylation sites further enhanced BAD's death-promoting activity. The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis.
Zha
J
J
Department of Medicine, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Harada
H
H
Yang
E
E
Jockel
J
J
Korsmeyer
S J
SJ
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D019281:Dimerization; D007377:Interleukin-3 / Q000494:pharmacology*; D008566:Membranes / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D048948:14-3-3 Proteins; D002352:Carrier Proteins; D007377:Interleukin-3; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D012694:Serine; D014446:Tyrosine 3-Monooxygenase