Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A:: A novel pharmacodynamic method for measuring aurora a activity
Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A:: A novel pharmacodynamic method for measuring aurora a activity
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DOI：
10.1158/0008-5472.can-07-0122
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Ecsedy, Jeffrey A.
中科院分区：
文献类型：
--
作者：
LeRoy, Patrick J.;Hunter, John J.;Ecsedy, Jeffrey A.
Aurora A 是一种丝氨酸/苏氨酸蛋白激酶，对于正常有丝分裂进程至关重要。 Aurora A 表达异常增加（常发生在人类癌症中）会导致有丝分裂异常，从而导致染色体不稳定并可能导致肿瘤发生。因此，Aurora A 作为抗癌治疗干预的潜在靶点受到了相当多的关注。 Aurora A 通过多种蛋白质的磷酸化来协调多种重要的有丝分裂活动，其中包括调节有丝分裂纺锤体微管稳定性的 TACC3。最近的研究发现，非洲爪蟾 (Ser 626) 和果蝇 (Ser(863)) TACC3 直向同源物中的保守丝氨酸被 Aurora A 磷酸化。我们表明，人 TACC3 (Ser 558) 上的保守丝氨酸也被 Aurora A 磷酸化。此外，在人类细胞中，Aurora A 对 TACC3 的磷酸化对于其正确定位到中心体和中心体至关重要。近端有丝分裂纺锤体。在培养的人肿瘤细胞中，用选择性小分子抑制剂 MLN8054 抑制 Aurora A 会导致 TACC3 以浓度依赖性方式错误定位，远离有丝分裂纺锤体。此外，对携带 HCT-116 人类肿瘤异种移植物的裸鼠口服 MLN8054 会导致 TACC3 剂量依赖性错误定位远离纺锤体极，这与肿瘤生长抑制相关。由于 TACC3 对有丝分裂纺锤体的定位取决于 Aurora A 介导的磷酸化，因此量化 TACC3 错误定位代表了一种新的药效学方法，用于测量接受 Aurora A 激酶抑制剂治疗的癌症患者中的 Aurora A 活性。
Aurora A is a serine/threonine protein kinase essential for normal mitotic progression. Aberrant increased expression of Aurora A, which occurs frequently in human cancers, results in abnormal mitoses leading to chromosome instability and possibly tumorigenesis. Consequently, Aurora A has received considerable attention as a potential target for anticancer therapeutic intervention. Aurora A coordinates several essential mitotic activities through phosphorylation of a variety of proteins, including TACC3, which modulates microtubule stabilization of the mitotic spindle. Recent studies identified a conserved serine in Xenopus (Ser 626) and Drosophila (Ser(863)) TACC3 orthologues that is phosphorylated by Aurora A. We show that this conserved serine on human TACC3 (Ser 558) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner. Furthermore, oral administration of MLN8054 to nude mice bearing HCT-116 human tumor xenografts caused a dose-dependent mislocalization of TACC3 away from spindle poles that correlated with tumor growth inhibition. As TACC3 localization to mitotic spindles depends on Aurora A-mediated phosphorylation, quantifying TACC3 mislocalization represents a novel pharmacodynamic approach for measuring Aurora A activity in cancer patients treated with inhibitors of Aurora A kinase.