Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-X(L)

Cell. 1996 Nov 15;87(4):619-28. doi: 10.1016/s0092-8674(00)81382-3.

Abstract

Extracellular survival factors alter a cell's susceptibility to apoptosis, often through posttranslational mechanisms. However, no consistent relationship has been established between such survival signals and the BCL-2 family, where the balance of death agonists versus antagonists determines susceptibility. One distant member, BAD, heterodimerizes with BCL-X(L) or BCL-2, neutralizing their protective effect and promoting cell death. In the presence of survival factor IL-3, cells phosphorylated BAD on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated BAD heterodimerized with BCL-X(L) at membrane sites to promote cell death. Phosphorylated BAD was sequestered in the cytosol bound to 14-3-3. Substitution of serine phosphorylation sites further enhanced BAD's death-promoting activity. The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 14-3-3 Proteins
  • Amino Acid Sequence
  • Carrier Proteins / metabolism*
  • Cell Death / physiology*
  • Cell Survival
  • Cytosol / metabolism
  • Dimerization
  • Interleukin-3 / pharmacology*
  • Membranes / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Serine / metabolism
  • Signal Transduction
  • Tyrosine 3-Monooxygenase*
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • 14-3-3 Proteins
  • Carrier Proteins
  • Interleukin-3
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Serine
  • Tyrosine 3-Monooxygenase