This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 LeRoy, P. J. Articles by Ecsedy, J. A. Search for Related Content PubMed PubMed Citation Articles by LeRoy, P. J. Articles by Ecsedy, J. A.

Localization of Human TACC3 to Mitotic Spindles Is Mediated by Phosphorylation on Ser⁵⁵⁸ by Aurora A: A Novel Pharmacodynamic Method for Measuring Aurora A Activity

Departments of ¹ Molecular and Cellular Oncology, ² Discovery Technologies, and ³ Cancer Pharmacology, Millennium Pharmaceuticals, Cambridge, Massachusetts

Requests for reprints: Jeffrey A. Ecsedy, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139. Phone: 617-444-1541; Fax: 617-551-8905; E-mail: jeffrey.ecsedy{at}mpi.com.

Aurora A is a serine/threonine protein kinase essential for normal mitotic progression. Aberrant increased expression of Aurora A, which occurs frequently in human cancers, results in abnormal mitoses leading to chromosome instability and possibly tumorigenesis. Consequently, Aurora A has received considerable attention as a potential target for anticancer therapeutic intervention. Aurora A coordinates several essential mitotic activities through phosphorylation of a variety of proteins, including TACC3, which modulates microtubule stabilization of the mitotic spindle. Recent studies identified a conserved serine in Xenopus (Ser⁶²⁶) and Drosophila (Ser⁸⁶³) TACC3 orthologues that is phosphorylated by Aurora A. We show that this conserved serine on human TACC3 (Ser⁵⁵⁸) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner. Furthermore, oral administration of MLN8054 to nude mice bearing HCT-116 human tumor xenografts caused a dose-dependent mislocalization of TACC3 away from spindle poles that correlated with tumor growth inhibition. As TACC3 localization to mitotic spindles depends on Aurora A–mediated phosphorylation, quantifying TACC3 mislocalization represents a novel pharmacodynamic approach for measuring Aurora A activity in cancer patients treated with inhibitors of Aurora A kinase. [Cancer Res 2007;67(11):5362–70]

This article has been cited by other articles:

				M.-S. Jang, J.-W. Sul, B.-J. Choi, S.-J. Lee, J.-H. Suh, N.-S. Kim, W. H. Kim, D.-S. Lim, C.-W. Lee, and E. Kim Negative Feedback Regulation of Aurora-A via Phosphorylation of Fas-associated Factor-1 J. Biol. Chem., November 21, 2008; 283(47): 32344 - 32351. [Abstract] [Full Text] [PDF]

				L.-Y. Lu, J. L. Wood, L. Ye, K. Minter-Dykhouse, T. L. Saunders, X. Yu, and J. Chen Aurora A Is Essential for Early Embryonic Development and Tumor Suppression J. Biol. Chem., November 14, 2008; 283(46): 31785 - 31790. [Abstract] [Full Text] [PDF]

				A. B. Fielding, I. Dobreva, P. C. McDonald, L. J. Foster, and S. Dedhar Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization J. Cell Biol., February 25, 2008; 180(4): 681 - 689. [Abstract] [Full Text] [PDF]

				A. R. Barr and F. Gergely Aurora-A: the maker and breaker of spindle poles J. Cell Sci., September 1, 2007; 120(17): 2987 - 2996. [Abstract] [Full Text] [PDF]