The phosphorylation status and anti-apoptotic activity of Bcl-2 are regulated by ERK and protein phosphatase 2A on the mitochondria

Yuki Tamura, Siro Simizu, Hiroyuki Osada

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109 Citations (Scopus)


Bcl-2 protein play important roles in the regulation of apoptosis. We previously reported that the phosphorylation of Bcl-2 was augmented by treatment with protein phosphatase 2A (PP2A) inhibitor; however, the kinase responsible for Bcl-2 phosphorylation had not yet been identified. In this study, we identified extracellular-signal-regulated kinase (ERK) as the responsible kinase for the phosphorylation of Bcl-2. We also found that the transmembrane region (TM) deleted form of Bcl-2 (Bcl-2ΔTM), which was unable to localize on the mitochondria was constitutively phosphorylated, whereas wild-type Bcl-2 that localized on the mitochondria, was present in its hypophosphorylated form. The phosphorylation of Bcl-2ΔTM was retarded by treatment with MAP kinase ERK kinase (MEK) inhibitor and PP2A did not bind to Bcl-2ΔTM. These observations suggest that Bcl-2ΔTM is constitutively phosphorylated by ERK, but is not dephosphorylated by PP2A in human tumor cell lines. The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.

Original languageEnglish
Pages (from-to)249-255
Number of pages7
JournalFEBS Letters
Issue number1-3
Publication statusPublished - 2004 Jul 2
Externally publishedYes


  • Apoptosis
  • Bcl-2
  • CPT, camptothecin
  • ERK, extracellular-signal-regulated kinase 1 and 2
  • Extracellular-signal-regulated kinase
  • JNK, c-Jun N-terminal kinase 1 and 2
  • MAPK, mitogen-activated protein kinase
  • Phosphorylation
  • Protein phosphatase 2A

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology


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