Non-centrosomal TPX2-Dependent Regulation of the Aurora A Kinase: Functional Implications for Healthy and Pathological Cell Division

Abstract

Aurora A has been extensively characterized as a centrosomal kinase with essential functions during cell division including centrosome maturation and separation and spindle assembly. However, Aurora A localization is not restricted to the centrosomes and compelling evidence support the existence of specific mechanisms of activation and functions for non-centrosomal Aurora A in the dividing cell. It has been now well established that spindle assembly involves an acentrosomal RanGTP-dependent pathway that triggers microtubule assembly and organization in the proximity of the chromosomes whether centrosomes are present or not. The mechanism involves the regulation of a number of NLS-containing proteins, generically called SAFS (Spindle Assembly Factors) that exert their functions upon release from karyopherins by RanGTP. One of them, the nuclear protein TPX2 interacts with and activates Aurora A upon release from importins by RanGTP. This basic mechanism triggers the activation of Aurora A in the proximity of the chromosomes potentially translating the RanGTP signaling gradient centered on the chromosome into an Aurora A phosphorylation network. Here, we will review our current knowledge on the RanGTP-dependent TPX2 activation of Aurora A away from centrosomes: from the mechanism of activation and its functional consequences on the kinase stability and regulation to its roles in spindle assembly and cell division. We will then focus on the substrates of the TPX2-activated Aurora A having a role in microtubule nucleation, stabilization, and organization. Finally, we will briefly discuss the implications of the use of Aurora A inhibitors in anti-tumor therapies in the light of its functional interaction with TPX2.

Keywords: Aurora A kinase; RanGTP; TPX2; cell division; importin; microtubule; phosphorylation; spindle.

Figure 1

TPX2 and Aurora A are cell cycle regulated proteins. Both proteins accumulate during G2/M and are degraded through the APC/C proteasome pathway at the end of mitosis. The relative protein levels of TPX2 (yellow triangle) and Aurora A (blue circle) in the different cell cycle phases are represented at the top. The localization of the two proteins during these cell cycle phases is represented in the drawings. In G2, TPX2 accumulates inside the nucleus whereas Aurora A accumulates at the centrosomes. During mitosis, both proteins co-localize along the spindle microtubules, and Aurora A also accumulates at the centrosomes.

Figure 2

(A) Schematic representation of the RanGTP-dependent interaction between TPX2 and Aurora A in the proximity of the chromosomes. The exchange factor RCC1 associated with the chromosomes generates a peak of RanGTP that releases TPX2 from the importin alpha and beta complex. TPX2 can then bind to Aurora A, promoting its autophosphorylation on Thr288 and kinase activation (blue color). The phosphatase PP1 can inactivate TPX2 free active Aurora A (mainly at the centrosome, gray color) through dephosphorylation but not the TPX2-activated Aurora A (blue color). (B) Direct consequences of the TPX2–Aurora A interaction. (C) Schematic representation of the mechanism driving acentrosomal RanGTP MT nucleation triggered by the complex TPX2–Aurora A. The TPX2–Aurora A complex associates with another specific complex containing XRHAMM-NEDD1–γ-TurC. In this macro complex the activated Aurora A phosphorylates NEDD1 at Ser405, an essential prerequisite for MT nucleation.