Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A.
Signaling pathways between cell surface receptors and the BCL-2 family of proteins regulate cell death. Survival factors induce the phosphorylation and inactivation of BAD, a proapoptotic member. Purification of BAD kinase(s) identified membrane-based cAMP-dependent protein kinase (PKA) as a BAD Ser-112 (S112) site-specific kinase. PKA-specific inhibitors blocked the IL-3-induced phosphorylation on S112 of endogenous BAD as well as mitochondria-based BAD S112 kinase activity. A blocking peptide that disrupts type II PKA holoenzyme association with A-kinase-anchoring proteins (AKAPs) also inhibited BAD phosphorylation and eliminated the BAD S112 kinase activity at mitochondria. Thus, the anchoring of PKA to mitochondria represents a focused subcellular kinase/substrate interaction that inactivates BAD at its target organelle in response to a survival factor.
Harada
H
H
Division of Molecular Oncology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Becknell
B
B
Wilm
M
M
Mann
M
M
Huang
L J
LJ
Taylor
S S
SS
Scott
J D
JD
Korsmeyer
S J
SJ
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases