The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway.
The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway.
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DOI：
10.18632/oncotarget.1931
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Fahlman RP
中科院分区：
文献类型：
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作者：
Eldeeb MA;Fahlman RP
凋亡途径的激活导致林恩酪氨酸激酶的半胱天冬酶切割，产生N端截短的林恩ΔN。该林恩ΔN片段已被证明对伊马替尼诱导的慢性粒细胞白血病（CML）K562细胞凋亡发挥负反馈作用。我们的研究集中在林恩ΔN稳定性和如何降低稳定性降低伊马替尼耐药性。由于蛋白水解产生的林恩ΔN具有亮氨酸作为N-末端氨基酸，我们假设林恩ΔN将通过N-末端规则途径降解。我们证明了林恩ΔN是不稳定的，它的稳定性取决于它的N-末端的身份。此外，我们还证实，通过抑制蛋白酶体或敲低UBR 1和UBR 2泛素E3连接酶，可以抑制林恩ΔN降解。重要的是，我们还证明了通过N端规则的林恩ΔN降解抵消了由林恩ΔN表达提供的K562细胞的伊马替尼抗性。总之，我们的数据表明，N端规则途径与CML中伊马替尼耐药有关的可能机制。由于林恩ΔN是N端规则底物，它提供了该途径也可以提供促凋亡功能的第一个实例，因为先前的报道目前仅证明了N端规则途径的抗凋亡作用。
The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated LynΔN. This LynΔN fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on LynΔN stability and how reduced stability reduces imatinib resistance. As the proteolytical generated LynΔN has a leucine as an N-terminal amino acid, we hypothesized that LynΔN would be degraded by the N-end rule pathway. We demonstrated that LynΔN is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that LynΔN degradation could be inhibited by either inhibiting the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that LynΔN degradation by the N-end rule counters the imatinib resistance of K562 cells provided by LynΔN expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With LynΔN being an N-end rule substrate, it provides the first example that this pathway can also provide a pro-apoptotic function as previous reports have currently only demonstrated anti-apoptotic roles for the N-end rule pathway.