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

Oncogene volume 18, pages 6635–6640 (1999)Cite this article

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-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 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.

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Abbreviations

EGF:

epidermal growth factor

IGF-I:

insulin-like growth factor-I

MAPK:

mitogen-activated protein kinase

PDGF:

platelet-derived growth factor

PI3K:

phosphatidylinositol 3-kinase

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Acknowledgements

The work has been supported by NIH grant (CA 64602). The authors were grateful to Dr G Nuñez for providing Flag-BAD expression vector, Dr UR Rapp for Raf-BXB constructs and Dr JS Gutkind for V12 Rac vector.

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Authors and Affiliations

  1. Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Xianjun Fang, Shuangxing Yu, Astrid Eder, Muling Mao & Gordon B Mills

  2. Department of Clinical Investigation, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Robert C Bast Jr

  3. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Douglas Boyd

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  1. Xianjun Fang
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Fang, X., Yu, S., Eder, A. et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18, 6635–6640 (1999). https://doi.org/10.1038/sj.onc.1203076

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