Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway

Oncogene. 1999 Nov 18;18(48):6635-40. doi: 10.1038/sj.onc.1203076.


The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of two sites, serine-112 (Ser-112) and serine-136 (Ser-136). Phosphorylation at either site results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. It has been shown that phosphorylation of BAD at Ser-136 is mediated by the serine/threonine protein kinase Akt-1/PKB which is downstream of phosphatidylinositol 3-kinase (PI3K). The signaling process leading to phophorylation of BAD at Ser-112 has not been identified. In this study, we show that phosphorylation of the two serine residues of BAD is differentially regulated. While Ser-136 phosphorylation is concordant with activation of Akt, Ser-112 phosphorylation does not correlate with Akt activation. Instead, we demonstrate that activated Ras and Raf, which are upstream of mitogen-activated protein kinases (MAPK), stimulate selective phosphorylation of BAD at Ser-112. Furthermore, phosphorylation of Ser-112, but not Ser-136 requires activation of the MAPK pathway as the MEK inhibitor, PD 98059, blocks EGF-, as well as activated Ras- or Raf-mediated phosphorylation of BAD at Ser-112. Therefore, the PI3K-Akt and Ras-MAPK pathways converge at BAD by mediating phosphorylation of distinct serine residues.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Serine / metabolism*
  • bcl-Associated Death Protein
  • ras Proteins / metabolism*


  • BAD protein, human
  • Bad protein, mouse
  • Carrier Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • Serine
  • ras Proteins