Phosphorylation of Ser/Thr residues is a well-established modulating mechanism of the pro-apoptotic function of the BH3-only protein Bim. However, nothing is known about the putative tyrosine phosphorylation of this Bcl-2 family member and its potential impact on Bim function and subsequent Bax/Bak-mediated cytochrome c release and apoptosis. As we have previously shown that the tyrosine kinase Lyn could behave as an anti-apoptotic molecule, we investigated whether this Src family member could directly regulate the pro-apoptotic function of Bim. In the present study, we show that Bim is phosphorylated onto tyrosine residues 92 and 161 by Lyn, which results in an inhibition of its pro-apoptotic function. Mechanistically, we show that Lyn-dependent tyrosine phosphorylation of Bim increases its interaction with anti-apoptotic members such as Bcl-xL, therefore limiting mitochondrial outer membrane permeabilization and subsequent apoptosis. Collectively, our data uncover one molecular mechanism through which the oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or the chemotherapeutic resistance of cancer cells.

中文翻译：

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致癌酪氨酸激酶Lyn损害了Bim的促凋亡功能。

Ser / Thr残基的磷酸化是仅BH3蛋白Bim促凋亡功能的公认调节机制。但是，有关此Bcl-2家族成员的酪氨酸磷酸化及其对Bim功能以及随后的Bax / Bak介导的细胞色素c释放和凋亡的潜在影响，一无所知。正如我们先前所显示的，酪氨酸激酶Lyn可以充当抗凋亡分子，我们研究了该Src家族成员是否可以直接调节Bim的促凋亡功能。在本研究中，我们显示Bim被Lyn磷酸化到酪氨酸残基92和161上，从而抑制了其促凋亡功能。从机理上讲，我们显示Bim的Lyn依赖性酪氨酸磷酸化增加了其与抗凋亡成员（如Bcl-xL，因此限制了线粒体外膜通透性和随后的细胞凋亡。总的来说，我们的数据揭示了一种分子机制，致癌酪氨酸激酶Lyn通过其负调控线粒体的凋亡途径，这可能有助于癌细胞的转化和/或化疗耐药性。