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J. Biol. Chem., Vol. 280, Issue 44, 36575-36583, November 4, 2005

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Polo-like Kinase 1-mediated Phosphorylation Stabilizes Pin1 by Inhibiting Its Ubiquitination in Human Cells^*

Frank Eckerdt12, Juping Yuan1, Krishna Saxena, Bernd Martin, Sven Kappel, Christine Lindenau, Andrea Kramer, Steffen Naumann, Sebastian Daum¶, Gunter Fischer¶, Ivan Dikic||, Manfred Kaufmann, and Klaus Strebhardt3

From the Department of Gynecology and Obstetrics and ^||Institute of Biochemistry II, Medical School, J. W. Goethe-University, Theodor-Stern-Kai 7, Frankfurt D-60590, Institute of Organic Chemistry, Marie-Curie Strasse 11, J. W. Goethe-University, Frankfurt D-60439, and ^¶Max-Planck Research Unit, Enzymology of Protein Folding, Weinbergweg 22, Halle D-06120, Germany

The Polo-like kinase 1 (Plk1) is a key regulator of mitosis. It is reported that the human peptidyl-prolyl cis/trans-isomerase Pin1 binds to Plk1 from mitotic cell extracts in vitro. Here we demonstrate that Ser-65 in Pin1 is the major site for Plk1-specific phosphorylation, and the polo-box domain of Plk1 is required for this phosphorylation. Interestingly, the phosphorylation of Pin1 by Plk1 does not affect its isomerase activity but rather is linked to its protein stability. Pin1 is ubiquitinated in HeLa S3 cells, and substitution of Glu for Ser-65 reduces the ubiquitination of Pin1. Furthermore, inhibition of Plk1 activity by expression of a dominant negative form of Plk1 or by transfection of small interfering RNA targeted to Plk1 enhances the ubiquitination of Pin1 and subsequently reduces the amount of Pin1 in human cancer cells. Since previous reports suggested that Plk1 is a substrate of Pin1, our work adds a new dimension to this interaction of two important mitotic regulators.

Received for publication, April 26, 2005 , and in revised form, August 15, 2005.

^* This work is supported by Nationales Genomforschungsnetz Grant N1KR-S12T29, Deutsche Krebshilfe Grant 10-1212-St 1, Deutsche Forschungsgemeinschaft Grant STR/8-1, the Messer Stiftung, and the Sander Stiftung. 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.

¹ Both authors contributed equally.

² To whom correspondence may be addressed: Dept. of Pharmacology, University of Colorado School of Medicine, Denver, CO 80262. E-mail: Frank.Eckerdt{at}UCHSC.edu. ³To whom correspondence may be addressed. Tel.: 49-69-63016894; Fax: 49-69-63016364; E-mail: Strebhardt{at}em.uni-frankfurt.de.

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