Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils.
Although important for apoptosis, the mechanism of Bax regulation is poorly understood. This study demonstrates that phosphorylation of Ser(184) regulates Bax activity. The phosphorylation required phosphatidylinositol 3-kinase/Akt activation and appeared to be mediated by Akt itself. In the serine-phosphorylated form, Bax was detected in the cytoplasm, could not be immunoprecipitated with the activation-specific antibody 6A7, and promoted heterodimerization with Mcl-1, Bcl-x(L), and A1. Apoptotic neutrophils possessed reduced levels of serine-phosphorylated Bax correlating with an increase in activated Bax as well as an increase in the amount of Bax found translocated to the mitochondria. We suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members.
Gardai
Shyra J
SJ
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Hildeman
David A
DA
Frankel
Steve K
SK
Whitlock
Ben B
BB
Frasch
S Courtney
SC
Borregaard
Niels
N
Marrack
Philippa
P
Bratton
Donna L
DL
Henson
Peter M
PM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000097:blood*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D010768:Phosphoserine; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt