Signaling pathways between cell surface receptors and the BCL-2 family of p
roteins regulate cell death. Survival factors induce the phosphorylation an
d 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-b
ased BAD S112 kinase activity. A blocking peptide that disrupts type II PKA
holoenzyme association with A-kinase-anchoring proteins (AKAPs) also inhib
ited BAD phosphorylation and eliminated the BAD S112 kinase activity at mit
ochondria. 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.