title: Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim.
abstract: The proapoptotic Bcl2 homology domain 3(BH3)-only protein Bim is controlled by stringent post-translational regulation, predominantly through alterations in phosphorylation status. To identify new kinases involved in its regulation, we carried out a yeast two-hybrid screen using a non-spliceable variant of the predominant isoform--Bim(EL)--as the bait and identified the regulatory subunit of cyclic-AMP-dependent protein kinase A--PRKAR1A--as an interacting partner. We also show that protein kinase A (PKA) is a Bim(EL) isoform-specific kinase that promotes its stabilization. Inhibition of PKA or mutation of the PKA phosphorylation site within Bim(EL) resulted in its accelerated proteasome-dependent degradation. These results might have implications for human diseases that are characterized by abnormally increased PKA activity, such as the Carney complex and dilated cardiomyopathy.
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: Moujalled
authors.forename: Ross
authors.initials: R
authors.lastname: Weston
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.forename: Robert
authors.initials: R
authors.lastname: Ninnis
authors.forename: Pranay
authors.initials: P
authors.lastname: Goel
authors.forename: Andrew
authors.initials: A
authors.lastname: Coley
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Hamsa
authors.initials: H
authors.lastname: Puthalakath
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D008565:Membrane Proteins; C517835:Prkar1a protein, mouse; D011518:Proto-Oncogene Proteins; D017868:Cyclic AMP-Dependent Protein Kinases