Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function
Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function
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DOI：
10.1038/sj.onc.1206792
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发表时间：
2003-10-02
期刊：
影响因子：
8
通讯作者：
Auberger, P
中科院分区：
文献类型：
--
作者：
Luciano, F;Jacquel, A;Auberger, P
Bim是Bcl-2家族的促凋亡成员，其仅与该家族共享BH 3结构域。三种Bim蛋白Bim-EL、Bim-L和Bim-S由同一转录物合成。我们在这里报告，Bim-EL磷酸化Erk 1/2时，通过蛋白酶体途径迅速降解。使用不同的细胞模型，我们的证据表明，丝氨酸69是必要的和足够的Erk 1/2介导的磷酸化和降解的Bim-EL。在K562细胞中，佛波醇1/2-肉豆蔻酸酯13-乙酸酯激活Erk 1/2，从而增加Bim-EL的磷酸化和蛋白酶体的降解，导致细胞存活，而Bcr-Abl抑制剂伊马替尼消除Bim-EL的磷酸化和降解，并诱导半胱天冬酶激活和凋亡。我们还表明，Bim-EL（S69 G）比Bim-EL-WT在K562细胞中更有效地促进凋亡。总之，我们的研究结果表明，磷酸化的Bim-EL的Erk 1/2丝氨酸69选择性地导致其蛋白酶体降解，因此代表了一个新的和重要的机制Bim的调节。
Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.