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Human Molecular Genetics Advance Access published online on October 9, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm298
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

ASAP is a novel substrate of the oncogenic mitotic kinase Aurora-A : phosphorylation on Ser625 is essential to spindle formation and mitosis

Magali Venoux1, Jihane Basbous1, Cyril Berthenet2, Claude Prigent3, Anne Fernandez2, Ned J. Lamb2 and Sylvie Rouquier1,*

1 Groupe Microtubules et Cycle Cellulaire, Institut de Génétique Humaine, CNRS UPR 1142, rue de la cardonille, 34396 Montpellier cédex 5, France. 2 Groupe Cycle Cellulaire et Myogenèse, Institut de Génétique Humaine, CNRS UPR 1142, rue de la cardonille, 34396 Montpellier cédex 5, France. 3 CNRS UMR 6061, Institut de Génétique et Développement, Université de Rennes I, IFR 140, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.

* To whom correspondence should be addressed at: Institut de Génétique Humaine, CNRS UPR 1142, rue de la cardonille, 34396 Montpellier cédex 5, France. Tel.: 33-4-99-61-99-35. Fax: 33-4-99-61-99-01. Email: rouquier{at}igh.cnrs.fr

Proper chromosome segregation is required to maintain the appropriate number of chromosomes from one cell generation to another and to prevent aneuploidy which is mainly found in solid cancers. A correct mitotic spindle is necessary to accomplish such a process. Aurora kinases play critical roles in chromosome segregation and cell division; their deregulation impairs spindle assembly, checkpoint function and cell division causing chromosome missegregation. These kinases have been implicated in tumorigenesis. Aurora- in particular has been identified as a cancer-susceptibility gene, is overexpressed in a number of tumors and is required for G2/M transition and spindle assembly. ASAP is a novel spindle-associated protein, the deregulation of which induces severe mitotic defects. We show here that ASAP is a novel substrate of Aurora-A kinase. We have identified serine 625 as the major phosphorylation site for Aurora-A in vivo and localized the phosphorylated form of ASAP to centrosomes from late G2 to telophase, and around the midbody during cytokinesis. AurA depletion induces a proteasome-dependent degradation of ASAP. ASAP depletion induces spindle defects rescued by expression of the phosphorylation-mimetic mutant ASAP-S625E and not by the non-phosphorylatable mutant ASAP-S625A. Microinjection of mono-specific S625 phospho-antibodies also impaired spindle formation and mitosis. These results strongly indicate that the phosphorylation of ASAP on S625 by Aurora-A is required for bipolar spindle assembly and is essential for a correct mitotic progression. All together, these results suggest that we have identified a novel Aurora-A substrate, pointing out ASAP as a new potential target for anti-tumoral drugs.


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