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J. Biol. Chem., Vol. 280, Issue 10, 9013-9022, March 11, 2005

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Identification of V23RalA-Ser¹⁹⁴ as a Critical Mediator for Aurora-A-induced Cellular Motility and Transformation by Small Pool Expression Screening^*

From the ^aDivision of Molecular and Genomic Medicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, the ^bGraduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, the ^gInstitute of Biotechnology in Medicine, National Yang-Ming University, Taipei 112, the ^hDepartment of Computer Science and Information Engineering, National Taiwan University, Taipei 106, the ^cDepartment of Physiology, National Cheng Kung University Medical College, Tainan 701, the ^dDepartment of Life Science, Chang Gung University, Tao-Yuan 333, the ^eInstitutes of Biopharmaceutical Science, National Yang-Ming University, Taipei 112, and the ^fDepartment of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan, R. O. C

Human Aurora kinases have three gene family members: Aurora-A, Aurora-B, and Aurora-C. It is not yet established what the specificity of these kinases are and what signals relayed by their reactions. Therefore, we employed small pool expression screening to search for downstream substrates of Aurora-A. Interestingly, all of the identified Aurora-A substrates were resistant to serve as substrates for Aurora-B or Aurora-C, suggesting that these Aurora family members may have distinct substrate specificity for propagation of diverse signaling pathways, even though they share a conserved catalytic kinase domain. Of the candidate substrates, Aurora-A could increase the functional activity of RalA. Mutational analysis revealed that RalA-Ser¹⁹⁴ was the phosphorylation site for Aurora-A. Ectopic expression of V23RalA-WT could enhance collagen I-induced cell migration and anchorage-independent growth in Madin-Darby canine kidney (MDCK) Aurora-A stable cell lines. In contrast, overexpression of V23RalA-S194A in MDCK Aurora-A-stable cell lines abolished the intrinsic migration and transformation abilities of Aurora-A. To our knowledge, this is the first systematic search for the downstream substrates of Aurora-A kinase. Moreover, these results support the notion that Aurora-A may act in concert with V23RalA through protein phosphorylation on Ser¹⁹⁴ to promote collagen I-induced cell motility and anchorage-independent growth in MDCK epithelial cells.

Received for publication, September 27, 2004 , and in revised form, December 16, 2004.

^* This work was supported by grants from the National Health Research Institutes and National Science Council (National Research Program for Genomic Medicine: NHRI93A1-NSCMM-11-5 to C.-Y. F. H.) and by the National Health Research Institutes (Grant NHRI-EX90-9001-BL to C.-K. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Table SI.

ⁱ To whom correspondence should be addressed: Tel.: 886-37-246-166 (ext. 35305/35306); Fax: 886-37-586-459; E-mail: chiying{at}nhri.org.tw.

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