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Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

Oncogene volume 26, pages 7700–7708 (2007)Cite this article

Abstract

RASSF1A (RAS-association domain family 1, isoform A) is a newer tumor suppressor that binds to and stabilizes microtubules as well as induces M-phase cell cycle arrest. Several other proteins that interact with and stabilize microtubules also undergo mitotic phase phosphorylation to regulate microtubule dynamics and M-phase cell cycle progression. Currently, however, there is a paucity of information regarding the phosphorylation status of RASSF1A and its regulation during mitosis. In this study, for the first time, we demonstrate that Aurora-A is a RASSF1A kinase and, to the best of our knowledge, this is also the first study reporting the identification of a kinase for RASSF1A. We show that the mitotic kinase Aurora-A directly interacts with and phosphorylates RASSF1 and that RASSF1A is phosphorylated by Aurora-A during mitosis. These findings therefore link an important oncogenic mitotic kinase to regulate RASSF1A tumor suppressor. Aurora-A appears to phosphorylate RASSF1A at Threonine202 and/or Serine203 that reside within the known microtubule-binding domain of RASSF1A. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of RASSF1A, disrupt RASSF1A interactions with microtubules and abolish its ability to induce M-phase cell cycle arrest. Our results further demonstrate that Aurora-A overexpression also interferes with RASSF1A-mediated growth suppression. In view of our results, we propose that Aurora-A-mediated phosphorylation of RASSF1A is a novel mechanism that regulates the ability of this tumor suppressor to interact with microtubules and modulate M-phase cell cycle progression.

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Acknowledgements

We thank Dr Peter C Keng, at the University of Rochester Cell Separation and Flow Cytometry Facility, for assisting in cell cycle analyses. This work was supported in part by the National Institutes of Health Grants CA113868, DK067271, CA113868 (to YH) and CA86945 (to MSS).

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  1. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, USA

    R Rong, L Y Jiang, M S Sheikh & Y Huang

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  1. R Rong
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  2. L Y Jiang
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Correspondence to Y Huang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Rong, R., Jiang, L., Sheikh, M. et al. Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation. Oncogene 26, 7700–7708 (2007). https://doi.org/10.1038/sj.onc.1210575

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