Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155

Jose M. Lizcano, Nick Morrice, Philip Cohen (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    260 Citations (Scopus)


    The interaction of BAD (Bcl-2/Bcl-X(L)-antagonist, causing cell death) with Bcl-2/Bcl-X(L) is thought to neutralize the antiapoptotic effects of the latter proteins, and may represent one of the mechanisms by which BAD promotes apoptosis. A variety of survival signals are reported to induce the phosphorylation of BAD at Ser112 or Ser136, triggering its dissociation from Bcl2/Bcl-X(L). Ser136 is thought to be phosphorylated by protein kinase B (PKB, also called Akt), which is activated when cells are exposed to agonists that stimulate phosphatidylinositol 3-kinase (PI3K). In contrast, Ser112 is reported to be phosphorylated by mitogen-activated protein (MAP) kinase-activated protein kinase-1 (MAPKAP-K1, also called RSK) and by cAMP-dependent protein kinase (PKA). Here we identify Ser155 as a third phosphorylation site on BAD. We find that Ser155 is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser155 prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. We also provide further evidence that MAPKAP-K1 mediates the phosphorylation of Ser112 in response to agonists that activate the classical MAP kinase pathway. However insulin-like growth factor 1, a potent activator of PI3K and PKB does not increase the phosphorylation of Ser136 in BAD-transfected HEK-293 cells, and nor is the basal level of Ser136 phosphorylation suppressed by inhibitors of PI3K.

    Original languageEnglish
    Pages (from-to)547-557
    Number of pages11
    JournalBiochemical Journal
    Issue number2
    Publication statusPublished - 15 Jul 2000


    • Apoptosis
    • Bcl-2
    • cAMP
    • MAP kinase
    • PKB

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology


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