QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online August 22, 2007
doi: 10.1242/10.1242/jcs.013136

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barr, A. R. Articles by Gergely, F. Search for Related Content PubMed PubMed Citation Articles by Barr, A. R. Articles by Gergely, F.

Aurora-A: the maker and breaker of spindle poles

Cancer Research UK Cambridge Research Institute, Department of Oncology, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK

View larger version (57K): [in this window] [in a new window]   Fig. 1. The centrosome cycle. At the beginning of G1 phase, cells contain a single centrosome with two perpendicularly aligned, closely associated centrioles. The two centrioles are not identical at this stage. The daughter centriole originates from the previous cell cycle, whereas the mother centriole (centriole with black cap) assembled at least two cell cycles ago. During G1 phase, the tight link (purple bar) between the centrioles is dissolved (centriole disengagement), but centrioles remain connected by a loose fibrous structure. Centriole disengagement is a prerequisite for centrosome duplication. In S phase, the centrosome duplicates simultaneously with DNA replication. Duplication involves the assembly of two new centrioles perpendicular to the existing centrioles. Note that at this point there are three different types of centriole in the cell: two newly formed centrioles, the daughter and the mother centriole. Next, the daughter centriole finally acquires the same molecular characteristics as the mother centriole and the fibrous tether between the mother and daughter centrioles is severed. Due to the tight link (purple bars) between the old centrioles and the newly formed ones, the two centrosomes are now engaged and prevented from further replication. In late G2 phase, the two centrosomes undergo maturation by recruiting additional PCM (grey circle) components to prepare for their role as spindle poles. The centrosomes then separate and move to the opposite side of the nucleus. Here, we show this as simultaneous with nuclear envelope breakdown (NEBD) and mitotic commitment; however, separation can be completed before or after NEBD (see text). Also, the timing and ordering of these events vary between cell types and organisms. After NEBD, the centrosomes start nucleating MT asters that capture chromosomes and form a bipolar spindle structure. The bipolar nature of mitosis ensures that each daughter cell inherits one centrosome. In dark-purple text, we list the experimental systems in which there is evidence for Aurora-A involvement in a particular step of the centrosome cycle (for more details, see Table 1).

View larger version (32K): [in this window] [in a new window]   Fig. 2. Subcellular localisation of the Aurora-A kinase during mitosis. Aurora-A remains in the spindle pole throughout mitosis. Aurora-A is green, microtubules are red and DNA is blue in the images. Bar, 10 µm.

View larger version (33K): [in this window] [in a new window]   Fig. 3. The role of Aurora-A in centrosome maturation. In preparation for its role as a mitotic spindle pole, the centrosome undergoes maturation, a process involving the expansion of its PCM (yellow) through the recruitment of cytoplasmic factors such as -tubulin (-tub). On the left-hand side is an `immature' centrosome – the PCM is sparse with little associated -tubulin. According to this model, in late G2 phase, the kinase CDK11 localises Plk1, which in turn recruits Aurora-A (Aur). Once in the centrosome, Aurora-A phosphorylates several factors (red ovals) that facilitate its autoactivation. The active Aurora-A kinase then recruits NDEL1. LATS2 kinase phosphorylates Ajuba, but this does not seem to be the mechanism by which it regulates centrosome maturation. The precise hierarchy of the targeting and activation of the proteins shown here is unknown, as is the factor that recruits -tubulin to the vertebrate centrosome during the process. In Drosophila, -tubulin is recruited to the centrosome by centrosomin (CNN), a protein that binds to Aurora-A and is dependent on the kinase for its centrosomal localisation (Terada et al., 2003).

View larger version (32K): [in this window] [in a new window]   Fig. 4. A model for how Aurora-A controls centrosomal MT stability. TACC protein is exclusively phosphorylated by Aurora-A (Aur) at the centrosome (in yellow). The targeting of TACC to the centrosome may be achieved in two ways: direct phosphorylation by Aurora-A or by Aurora-A-phosphorylated NDEL1. TACC can only bind MTs (in green) when complexed with the MT-stabilising protein ch-TOG/XMAP215 (TOG), and together they are required to counter the MT-destabilising activity of MCAK/XKCM1 (MCAK). Aurora-A-mediated phosphorylation of TACC promotes the binding of TACC-TOG to MT minus-ends, where they protect MTs from MCAK-induced destabilisation. Once bound to MT ends, TACC becomes dephosphorylated. The TACC-TOG complex could have additional roles on the plus-ends of MTs. It therefore stabilises centrosome-associated MTs in two ways: by protecting their minus ends from MCAK activity and by stabilising MTs as they polymerise. When endogenous TACC is replaced with non-phosphorylatable TACC, centrosomal TACC levels may be reduced. Furthermore, TACC-TOG fails to accumulate on MT minus-ends and centrosomal MTs are no longer shielded from MCAK activity.

View larger version (38K): [in this window] [in a new window]   Fig. 5. Aurora-A coordinates centrosome- and chromatin-independent spindle assembly. Aurora-A-coated beads assemble bipolar spindles in Xenopus egg extracts in the absence of chromatin and centrosomes, in combination with the EXTAH complex. Aurora-A (Aur) phosphorylates Tpx2, which in turn leads to the autophosphorylation of Aurora-A and hence activation of its kinase activity (in orange). Activation of Aurora-A kinase recruits other proteins of the EXTAH complex, which are required for MT nucleation (TuRC), MT stabilisation (XMAP215) and MT bundling (HURP). Eg5 may provide motor activity, which, in combination with the MT activities mentioned, could slide apart, cross-link and stabilise MTs emanating from adjacent Aurora-A-coated beads. Once a bipolar spindle is formed, members of the EXTAH complex may help maintain the stability of this structure.