title: Control of Aurora-A stability through interaction with TPX2.
abstract: 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.
authors.affiliation: Institute of Molecular Biology and Pathology, CNR, c/o Sapienza University of Rome, Via degli Apuli 4, 00185, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Giubettini
authors.forename: Italia A
authors.initials: IA
authors.lastname: Asteriti
authors.forename: Jacopo
authors.initials: J
authors.lastname: Scrofani
authors.forename: Maria
authors.initials: M
authors.lastname: De Luca
authors.forename: Catherine
authors.initials: C
authors.lastname: Lindon
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.forename: Giulia
authors.initials: G
authors.lastname: Guarguaglini
mesh_terms: D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016195:G2 Phase; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C122167:TPX2 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases