Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Biol. Chem. 277 (26): 23742-23746

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of Aurora Kinases as RasGAP Src Homology 3 Domain-binding Proteins*

Véronique GigouxDagger , Sébastien L'Hoste§, Françoise RaynaudDagger , Jacques Camonis§, and Christiane GarbayDagger ||

From the Dagger  Laboratoire de Pharmacochimie Moléculaire et Structurale, CNRS FRE2463-INSERM U266, UFR des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France and the § Laboratoire de Transduction du Signal et Oncogenèse, INSERM U528-Institut Curie, 26 rue d'Ulm, 75005 Paris, France

The GTPase-activating protein RasGAP functions as both a negative regulator and an effector of Ras proteins. In tumor cells, RasGAP is no longer able to deactivate oncogenic Ras proteins, and its effector function becomes predominant. As RasGAP itself has no obvious enzymatic function that may explain this effector function, we looked for downstream RasGAP effectors that could fulfill this role. We looked for the existence of RasGAP Src homology 3 (SH3) domain partners as this domain is involved in the regulation of cell proliferation and has an anti-apoptotic effect. We report here the identification of a new RasGAP SH3 domain-binding protein, named Aurora. This Drosophila melanogaster Ser/Thr kinase has three human orthologs called Aurora/Ipl1-related kinase or HsAIRK-1, -2, and -3. Coimmunoprecipitation experiments in COS cells confirmed that HsAIRK-1 and HsAIRK-2 both interact with RasGAP. RasGAP pull-down experiments showed that it interacts with HsAIRK-1 in G2/M HeLa cells. We also demonstrated that RasGAP binds to the kinase domain of Aurora and that this interaction inhibits the kinase activity of HsAIRK-1 and HsAIRK-2. Finally we showed that RasGAP forms a ternary complex with HsAIRK and survivin. This complex may be involved in the regulation of the balance between cell division and apoptosis.

* This study was supported by grants from the Association pour la Recherche sur le Cancer (grant to V. G. and financial support ARC4397 to INSERM U528), from the Ligue Nationale contre le Cancer (comité de Paris, LA07), and from the European Community (CEE QLK3-CT-1999-00875).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the Ministère de l'Enseignement Supérieur, de la Recherche et de la Technologie.

|| To whom correspondence should be addressed. Tel.: 33-1-53-73-95-60; Fax: 33-1-53-73-98-75; E-mail: garbay@pharmacie.univ-paris5.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ras-Driven Transcriptome Analysis Identifies Aurora Kinase A as a Potential Malignant Peripheral Nerve Sheath Tumor Therapeutic Target.
A. V. Patel, D. Eaves, W. J. Jessen, T. A. Rizvi, J. A. Ecsedy, M. G. Qian, B. J. Aronow, J. P. Perentesis, E. Serra, T. P. Cripe, et al. (2012)
Clin. Cancer Res. 18, 5020-5030
   Abstract »    Full Text »    PDF »
Aurora-A Phosphorylates, Activates, and Relocalizes the Small GTPase RalA.
K.-H. Lim, D. C. Brady, D. F. Kashatus, B. B. Ancrile, C. J. Der, A. D. Cox, and C. M. Counter (2010)
Mol. Cell. Biol. 30, 508-523
   Abstract »    Full Text »    PDF »
PHA-680632, a Novel Aurora Kinase Inhibitor with Potent Antitumoral Activity..
C. Soncini, P. Carpinelli, L. Gianellini, D. Fancelli, P. Vianello, L. Rusconi, P. Storici, P. Zugnoni, E. Pesenti, V. Croci, et al. (2006)
Clin. Cancer Res. 12, 4080-4089
   Abstract »    Full Text »    PDF »
Receptor for Hyaluronan-Mediated Motility Correlates with Centrosome Abnormalities in Multiple Myeloma and Maintains Mitotic Integrity.
C. A. Maxwell, J. J. Keats, A. R. Belch, L. M. Pilarski, and T. Reiman (2005)
Cancer Res. 65, 850-860
   Abstract »    Full Text »    PDF »
Identification of the Substrates and Interaction Proteins of Aurora Kinases from a Protein-Protein Interaction Model.
A.-C. Tien, M.-H. Lin, L.-J. Su, Y.-R. Hong, T.-S. Cheng, Y.-C. G. Lee, W.-J. Lin, I. H. Still, and C.-Y. F. Huang (2004)
Mol. Cell. Proteomics 3, 93-104
   Abstract »    Full Text »    PDF »
Targeting Aurora-2 Kinase in Cancer.
S. L. Warner, D. J. Bearss, H. Han, and D. D. Von Hoff (2003)
Mol. Cancer Ther. 2, 589-595
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882