Regulation and functions of nuclear Aurora-A and their dependence on TPX2

Aurora-A is a mitotic kinase frequently overexpressed in cancer and well known for its role in mitotic entry, centrosome maturation, and spindle assembly (Nikonova et al., 2013; Lin et al., 2020; Du et al., 2021). However, recent findings have uncovered additional interphasic functions of Aurora-A, independent from its kinase activity, particularly associated with its nuclear localization (Naso et al., 2021). These nuclear functions have been implicated in oncogenic processes, particularly in breast cancer, where Aurora-A can promote the transcription of key oncogenes such as c-Myc and FOXM1 (Zheng et al., 2016; Yang et al., 2017). Among Aurora-A interactors, the microtubule-associated protein TPX2 is known to activate and stabilize the kinase on spindle microtubules and protect it from proteasomal degradation (Kufer et al., 2002; Bayliss et al., 2003; Gruss & Vernos, 2004; Giubettini et al., 2011; Levinson, 2018). Intriguingly, TPX2 is predominantly nuclear in interphase and is frequently co-overexpressed with Aurora-A in several cancer types, suggesting a potential role in modulating Aurora-A nuclear localization and its oncogenic potential. On these bases, the Aurora-A/TPX2 complex has been proposed to function as an oncogenic holoenzyme and represents a promising target in anti-cancer strategies (Asteriti et al., 2010). Despite these findings, the mechanisms regulating Aurora-A nucleus/cytoplasmic trafficking, and the molecular pathways underlying its oncogenic nuclear functions, remain poorly understood. The aim of my PhD project is to investigate the mechanisms controlling the nuclear accumulation of Aurora-A and to define the role of TPX2 in this process and in Aurora-A-dependent oncogenic functions. By addressing these aspects, this work aims to provide mechanistic insight into the spatial regulation of Aurora-A in cancer and to contribute to the identification of novel actionable targets for the development of selective therapeutic strategies against its nuclear, non-canonical functions.