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 Mills

Research output: Contribution to journalArticle

212 Citations (Scopus)

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
StatePublished - Nov 18 1999
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinases
Serine
Phosphorylation
Phosphatidylinositol 3-Kinase
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
Epidermal Growth Factor
Cytoplasm

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Fang, X., Yu, S., Eder, A., Mao, M., Bast, R. C., Boyd, D., & Mills, G. (1999). Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene, 18(48), 6635-6640.

Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. / Fang, Xianjun; Yu, Shuangxing; Eder, Astrid; Mao, Muling; Bast, Robert C.; Boyd, Douglas; Mills, Gordon.

In: Oncogene, Vol. 18, No. 48, 18.11.1999, p. 6635-6640.

Research output: Contribution to journalArticle

Fang, X, Yu, S, Eder, A, Mao, M, Bast, RC, Boyd, D & Mills, G 1999, 'Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway', Oncogene, vol. 18, no. 48, pp. 6635-6640.
Fang X, Yu S, Eder A, Mao M, Bast RC, Boyd D et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene. 1999 Nov 18;18(48):6635-6640.
Fang, Xianjun ; Yu, Shuangxing ; Eder, Astrid ; Mao, Muling ; Bast, Robert C. ; Boyd, Douglas ; Mills, Gordon. / Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. In: Oncogene. 1999 ; Vol. 18, No. 48. pp. 6635-6640.
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