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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.

Pubmed ID: 10230394

Authors

  • Harada H
  • Becknell B
  • Wilm M
  • Mann M
  • Huang LJ
  • Taylor SS
  • Scott JD
  • Korsmeyer SJ

Journal

Molecular cell

Publication Data

April 27, 1999

Associated Grants

  • Agency: NCI NIH HHS, Id: 5R01 CA 50239-10

Mesh Terms

  • Animals
  • Apoptosis
  • Carrier Proteins
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Cyclic AMP-Dependent Protein Kinases
  • Enzyme Activation
  • Enzyme Inhibitors
  • Interleukin-3
  • Mitochondria
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2
  • Signal Transduction
  • Tumor Cells, Cultured
  • bcl-Associated Death Protein