LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy
LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy
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DOI：
10.1242/jcs.092304
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发表时间：
2012-03-01
影响因子：
4
通讯作者：
Shah, Kavita
中科院分区：
文献类型：
--
作者：
Johnson, Emmanuel O.;Chang, Kuei-Hua;Shah, Kavita
Aurora A在大多数乳腺癌中过表达。除BRCA 1和PHLDA 1外，在乳腺癌中没有已知的致癌Aurora A底物。在这项研究中，化学遗传学的方法被用来确定极光A的恶性目标，这表明LIMK 2作为一种新的极光A底物。Aurora A通过在S283、T494和T505处直接磷酸化来调节LIMK 2激酶活性、亚细胞定位和蛋白水平。作为响应，LIMK 2也积极调节Aurora A的水平，从而参与正反馈回路，促进Aurora-A介导的致癌途径。最重要的是，LIMK 2消融完全消除了Aurora-A介导的裸鼠肿瘤发生，表明LIMK 2是Aurora-A的关键致癌效应子。此外，LIMK 2消融与Aurora A的抑制在促进细胞死亡中协同作用。最后，Aurora-A介导的LIMK 2上调似乎是许多癌症中的常见机制。因此，LIMK 2抑制或消融是调节癌症中Aurora A失调的替代方法。
Aurora A is overexpressed in majority of breast carcinomas. With the exception of BRCA1 and PHLDA1, no oncogenic Aurora A substrates are known in breast cancer. In this study, a chemical genetic approach was used to identify malignant targets of Aurora A, which revealed LIMK2 as a novel Aurora A substrate. Aurora A regulates LIMK2 kinase activity, subcellular localization and protein levels by direct phosphorylation at S283, T494 and T505. In response, LIMK2 also positively regulates the level of Aurora A, thereby engaging in a positive-feedback loop, promoting Aurora-A-mediated oncogenic pathways. Most importantly, LIMK2 ablation fully abrogates Aurora-A-mediated tumorigenesis in nude mice, suggesting that LIMK2 is a key oncogenic effector of Aurora A. Furthermore, LIMK2 ablation acts synergistically with inhibition of Aurora A in promoting cell death. Finally, Aurora-A-mediated upregulation of LIMK2 appears to be a common mechanism in many cancers. LIMK2 inhibition or ablation is therefore an alternative approach for modulating Aurora A deregulation in cancer.