Control of Aurora-A stability through interaction with TPX2

被引:69
|
作者
Giubettini, Maria [1 ]
Asteriti, Italia A. [1 ]
Scrofani, Jacopo [1 ]
De Luca, Maria [1 ,2 ]
Lindon, Catherine [2 ]
Lavia, Patrizia [1 ]
Guarguaglini, Giulia [1 ]
机构
[1] Univ Roma La Sapienza, CNR, Inst Mol Biol & Pathol, I-00185 Rome, Italy
[2] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England
关键词
Aurora-A; mitosis; protein degradation; TPX2; MITOTIC SPINDLE; PROTEIN-KINASE; CELL-DIVISION; ANAPHASE; ACTIVATION; MECHANISM; INTEGRITY; PATHWAY; TARGETS; CANCER;
D O I
10.1242/jcs.075457
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Aurora-A kinase has well-established roles in spindle assembly and function and is frequently overexpressed in tumours. Its abundance is cell cycle regulated, with a peak in G2 and M phases, followed by regulated proteolysis at the end of mitosis. The microtubule-binding protein TPX2 plays a major role in regulating the activity and localisation of Aurora-A in mitotic cells. Here, we report a novel regulatory role of TPX2 and show that it protects Aurora-A from degradation both in interphase and in mitosis in human cells. Specifically, Aurora-A levels decrease in G2 and prometaphase cells silenced for TPX2, whereas degradation of Aurora-A is impaired in telophase cells overexpressing the Aurora-A-binding region of TPX2. The decrease in Aurora-A in TPX2-silenced prometaphases requires proteasome activity and the Cdh1 activator of the APC/C ubiquitin ligase. Reintroducing either full-length TPX2, or the Aurora-A-binding region of TPX2, but not a truncated TPX2 mutant lacking the Aurora-A-interaction domain, restores Aurora-A levels in TPX2-silenced prometaphases. The control by TPX2 of Aurora-A stability is independent of its ability to activate Aurora-A and to localise it to the spindle. These results highlight a novel regulatory level impinging on Aurora-A and provide further evidence for the central role of TPX2 in regulation of Aurora-A.
引用
收藏
页码:113 / 122
页数:10
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