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

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• 作者：Tamura ; Yuki ; Simizu ; Siro ; Osada ; Hiroyuki
• 关键词：Apoptosis ; Bcl-2 ; Protein phosphatase 2A ; Extracellular-signal-regulated kinase ; Phosphorylation ; CPT ; camptothecin ; ERK ; extracellular-signal-regulated kinase 1 and 2 ; JNK ; c-Jun N-terminal kinase 1 and 2 ; MAPK ; mitogen-activated protein kinase ; MEK ; MAP
• 刊名：FEBS Letters
• 出版年：2004
• 出版时间：July 2, 2004
• 年：2004
• 卷：569
• 期：1-3
• 页码：249-255
• 全文大小：331 K

文摘

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.