4.5 Article

Control of Aurora-A stability through interaction with TPX2

Journal

JOURNAL OF CELL SCIENCE
Volume 124, Issue 1, Pages 113-122

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.075457

Keywords

Aurora-A; mitosis; protein degradation; TPX2

Categories

Funding

  1. MIUR-Italian Ministry for University and Research [200879X9N9]
  2. AIRC-Italian Association for Cancer Research
  3. Assicurazioni Generali Spa and Fondazione Roma-Terzo Settore
  4. Cancer Research UK
  5. MRC
  6. MIUR
  7. MRC [G120/892] Funding Source: UKRI
  8. Medical Research Council [G120/892] Funding Source: researchfish

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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.

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