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

Xianjun Fang, Shuangxing Yu, Astrid Eder, Muling Mao, Robert C. Bast, Douglas Boyd, Gordon B. Mills

Research output: Contribution to journalArticlepeer-review

223 Scopus citations

Abstract

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-X(L) 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 phosphorylation 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.

Original languageEnglish (US)
Pages (from-to)6635-6640
Number of pages6
JournalOncogene
Volume18
Issue number48
DOIs
StatePublished - Nov 18 1999
Externally publishedYes

Keywords

  • Akt
  • Apoptosis
  • BAD
  • MAPK
  • Phosphorylation
  • Ras

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway'. Together they form a unique fingerprint.

Cite this