Review Article | Published:

The cellular geography of Aurora kinases

Nature Reviews Molecular Cell Biology volume 4, pages 842854 (2003) | Download Citation

Subjects

Abstract

Aurora is the name given to a family of highly conserved protein kinases with essential roles in many aspects of cell division. Yeasts have a single Aurora kinase, whereas mammals have three: Aurora A, B and C. During mitosis, Aurora kinases regulate the structure and function of the cytoskeleton and chromosomes and the interactions between these two at the kinetochore. They also regulate signalling by the spindle-assembly checkpoint pathway and cytokinesis. Perturbation of Aurora kinase expression or function might lead to cancer.

Key points

  • The Aurora family of conserved serine/threonine kinases perform essential functions during cell division. The three mammalian paralogues are very similar in sequence, but differ significantly in their localization, function, substrates and regulatory partners.

  • Aurora A is mainly associated with the spindle poles during mitosis, where it is required for centrosome separation and maturation. Spindle assembly requires that targeting protein for XKLP 2 (TPX2) targets Aurora A to spindle pole microtubules through a mechanism that requires Ran–GTP. Aurora A also functions in meiosis, promoting oocyte maturation, polar-body extrusion, spindle positioning and exit from metaphase I.

  • Regulation of Aurora A occurs through phosphorylation/dephosphorylation and degradation. Protein phosphatase 1 negatively regulates Aurora and this interaction is modulated by TPX2. The Cdh1/Fizzy-related form of anaphase-promoting complex/cyclosome (APC/C) targets Aurora for degradation in late mitosis.

  • Aurora B is a chromosomal-passenger protein with multiple functions in mitosis. Inner centromere protein (INCENP) and survivin, two other components of the passenger complex, function as targeting and regulatory factors for the kinase. Aurora B is required for phosphorylation of histone 3, targeting of condensin and normal chromosome compaction. It has also been recently shown to be essential for chromosome biorentation, kinetochore–microtubule interactions and the spindle-assembly checkpoint.

  • Aurora B is essential for completion of cytokinesis. Myosin II regulatory chain, vimentin, desmin and glial fibrillary acidic protein are among its cleavage furrow substrates. Aurora B phosphorylates MgcRacGAP transforming it into an activator of RhoA in the contractile ring.

  • Much less is known about Aurora-C kinases, other than that they seem to be preferentially expressed in meiotic cells — they are not discussed here in detail.

  • Misexpression of Aurora kinases is linked to cancer, but their possible role in carcinogenesis is yet to be elucidated.

  • During the cell cycle, Aurora kinases travel to their subcellular targets aided by their binding partner-substrates, INCENP, survivin and TPX2. This provides an additional level of regulation that might be essential for the choreography of mitotic events.

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Acknowledgements

The authors want to thank M. O. Lombardia, University of York, for his generous help and advice on the analysis and modelling of the structural similarities of the kinase domains and for his contribution to figures 1 and 2. Work in the W.C.E. laboratory is supported by The Wellcome Trust, of which W.C.E. is a Principal Research Fellow.

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Affiliations

  1. Wellcome Trust Centre for Cell Biology, Institute for Cell and Molecular Biology, Kings Buildings, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, Scotland, UK.  mar.carmena@ed.ac.uk;bill.earnshaw@ed.ac.uk  

    • Mar Carmena
    •  & William C. Earnshaw

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Glossary

CENTROSOME

The main microtubule-organizing centre of cells.

CHROMOSOME CONDENSATION

On entry into mitosis, chromosomes become compacted or 'condensed'. This is especially apparent in higher eukaryotes.

KINETOCHORE

A proteinaceous structure that connects each chromatid to the spindle microtubules.

MICROTUBULE

A hollow tube, 25 nm in diameter, that is formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.

PARALOGUES

Genes with related structure and function within the same species.

HETEROCHROMATIN

A condensed form of chromatin containing few expressed genes and often rich in repeated DNA elements. It is commonly, but not exclusively, found around the centromere.

MIDBODY

A dense bundle of microtubules embedded in an electron-dense matrix. This is derived from the central spindle during late telophase and is localized within the intercellular bridge during cytokinesis.

SPINDLE MIDZONE

Organized bundles of antiparallel microtubules that form during anaphase and telophase. Signals from the central spindle are thought to be important for signalling the location of the cleavage furrow.

SPINDLE POLE

The region at the end of the mitotic spindle where minus ends of the microtubules are clustered together as a result of the action of various microtubule motor proteins. In most animal cells, the spindle pole is centered around a centrosome. Plant spindles in somatic cells, however, lack focused centrosomes.

MITOTIC FIGURES

A term used by cytologists to describe mitotic cells visualized under the microscope.

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation — by nucleases — of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

CENTRIOLE

A cylindrical array of 9 bundles of microtubules (usually triplets in animal cells) with other specialized appendages. Two centrioles, referred to as mother and daughter, are found in the centre of centrosomes in animal cells.

PERICENTRIOLAR MATERIAL

Region of the cytoplasm surrounding the two centrioles in the centrosome. This is the region where microtubule assembly is initiated by γ-tubulin.

γ-TUBULIN

A specialized isoform of tubulin that, together with several associated proteins, forms a ring-like complex that directs the initiation of microtubule assembly.

IMPORTINS

A class of protein discovered because of the ability of the members to act as adaptors and carriers during the import (and export) of proteins across the nuclear envelope. Importins are now known to have a second role in regulating the assembly of the mitotic spindle.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

MPF

(Maturation-promoting factor/M-phase promoting factor). The complex of a B-type cyclin Cks1, and cyclin-dependent kinase 1, which is also referred to as Cdc2 or p34, depending on the species. This is the main enzyme that is responsible for entry into M phase in both meiosis and mitosis.

POLAR BODY

Either of the two small cells, each being formed during the successive divisions of meiosis, that forms as a result of division of a primary oocyte during its development to a mature ovum. The cytoplasm divides unequally during each division — the polar body is much smaller than the developing oocyte. Polar bodies eventually degenerate.

METAPHASE PLATE

The dynamic group of chromosomes positioned roughly midway between spindle poles prior to the onset of anaphase. These chromosomes have formed proper bipolar attachments (that is, their sister chromatids are connected to opposite spindle poles).

PROTEASOME

Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

ASTRAL MICROTUBULES

Microtubules that extend in a radial array outwards from the spindle poles, excluding those microtubules that attach to kinetochores or form part of the organized spindle midzone.

SISTER CHROMATIDS

Chromosomes that have been duplicated during S phase. Sister chromatids are held together by cohesins until metaphase.

CONGRESSION

The movement of correctly attached mitotic chromosomes to the metaphase plate at the midzone of the mitotic spindle.

CONDENSIN

A complex of two SMC (structural maintenance of chromosomes) proteins and three auxiliary subunits that can bind to and supercoil DNA. Condensin directs the binding of other non-histone proteins to mitotic chromosomes, and although not essential for mitotic chromatin condensation, it is essential for the structural integrity of mitotic chromosomes.

CHIASMATA

Connections formed between homologous chromosomes that are thought to be the point of the interchange that is involved in crossing over.

COHESIN

A protein complex that tethers sister chromatids together from the time they are created (during DNA replication) until cohesin cleavage at the onset of anaphase.

CLEAVAGE FURROW

A region of the plasma membrane in higher eukaryotic cells that ingresses to separate the two daughter cells at cytokinesis; contraction in this region is driven by actin and myosin filament interaction.

INTERMEDIATE FILAMENT

A cytoskeletal filament, typically 10 nm in diameter, that occurs in higher eukaryotic cells. The protein composition of intermediate filaments varies between cell types. Examples of intermediate filament proteins are keratins, vimentin and desmin.

ANEUPLOIDY

The ploidy of a cell refers to the number of sets of chromosomes that it contains. Aneuploid karyotypes are those whose chromosome complements are not a simple multiple of the haploid set.

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DOI

https://doi.org/10.1038/nrm1245

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