PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer
PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer
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DOI：
10.1242/jcs.084970
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发表时间：
2011-08-15
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激酶在大多数乳腺癌中过表达。化学遗传学方法用于鉴定Aurora A的恶性靶标，其揭示了pleckstrin同源样结构域蛋白PHLDA 1作为Aurora A底物。我们的研究证实，PHLDA 1下调是乳腺癌的一个强有力的预后预测因子。我们进一步表明，下调PHLDA 1与雌激素受体（ER）在乳腺癌中的表达。Aurora A直接磷酸化PHLDA 1，导致其降解。PHLDA 1也负调节极光A，从而触发反馈回路。我们证明了PHLDA 1上调强烈拮抗Aurora-A介导的致癌途径的潜在机制，从而揭示了PHLDA 1降解是Aurora-A促进乳腺恶性肿瘤的关键机制。因此，毫不奇怪，PHLDA 1上调与Aurora A抑制在促进细胞死亡中协同作用。因此，PHLDA 1过表达可能是调节乳腺癌中Aurora A失调的另一种方法。最后，这项研究发现了Aurora A活性位点的突变，使其适合化学遗传方法。Aurora B也需要类似的突变，这表明这种改良的方法可以扩展到迄今为止还不适合这种方法的其他激酶。
Aurora A kinase is overexpressed in the majority of breast carcinomas. A chemical genetic approach was used to identify the malignant targets of Aurora A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an Aurora A substrate. PHLDA1 downregulation is a powerful prognostic predictor for breast carcinoma, which was confirmed in our study. We further show that downregulation of PHLDA1 is associated with estrogen receptor (ER) expression in breast carcinoma. Aurora A directly phosphorylates PHLDA1 leading to its degradation. PHLDA1 also negatively regulates Aurora A, thereby triggering a feedback loop. We demonstrate the underlying mechanisms by which PHLDA1 upregulation strongly antagonizes Aurora-A-mediated oncogenic pathways, thereby revealing PHLDA1 degradation as a key mechanism by which Aurora A promotes breast malignancy. Thus, not surprisingly, PHLDA1 upregulation acts synergistically with Aurora A inhibition in promoting cell death. PHLDA1 overexpression might therefore be an alternative method to modulate Aurora A deregulation in breast carcinoma. Finally, this study led to the discovery of a mutation in the Aurora A active site that renders it amenable to the chemical genetic approach. Similar mutations are required for Aurora B, suggesting that this modified approach can be extended to other kinases that have hitherto not been amenable to this methodology.