Essential role of A-kinase anchor protein 121 for cAMP signaling to mitochondria.
A-Kinase anchor proteins (AKAPs) immobilize and concentrate protein kinase A (PKA) isoforms at specific subcellular compartments. Intracellular targeting of PKA holoenzyme elicits rapid and efficient phosphorylation of target proteins, thereby increasing sensitivity of downstream effectors to cAMP action. AKAP121 targets PKA to the cytoplasmic surface of mitochondria. Here we show that conditional expression of AKAP121 in PC12 cells selectively enhances cAMP.PKA signaling to mitochondria. AKAP121 induction stimulates PKA-dependent phosphorylation of the proapoptotic protein BAD at Ser(155), inhibits release of cytochrome c from mitochondria, and protects cells from apoptosis. An AKAP121 derivative mutant that localizes on mitochondria but does not bind PKA down-regulates PKA signaling to the mitochondria and promotes apoptosis. These findings indicate that PKA anchored by AKAP121 transduces cAMP signals to the mitochondria, and it may play an important role in mitochondrial physiology.
Affaitati
Adele
A
Dipartimento di Biologia e Patologia Molecolare e Cellulare, BioGeM Consortium, Istituto di Endocrinologia ed Oncologia Sperimentale CNR, Facoltà di Medicina, Universitá Federico II, via S. Pansini 5, 80131 Napoli, Italy.
Cardone
Luca
L
de Cristofaro
Tiziana
T
Carlucci
Annalisa
A
Ginsberg
Michael D
MD
Varrone
Stelio
S
Gottesman
Max E
ME
Avvedimento
Enrico V
EV
Feliciello
Antonio
A
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C486332:Akap1 protein, rat; D002352:Carrier Proteins; D017931:DNA Primers; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020169:Caspases