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J. Biol. Chem., Vol. 279, Issue 6, 4612-4624, February 6, 2004

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Characterization of Cyclin L2, a Novel Cyclin with an Arginine/Serine-rich Domain

PHOSPHORYLATION BY DYRK1A AND COLOCALIZATION WITH SPLICING FACTORS^*

Katrin de Graaf, Paul Hekerman, Oliver Spelten, Andreas Herrmann, Len C. Packman¶, Konrad Büssow||, Gerhard Müller-Newen, and Walter Becker**

From the Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der RWTH Aachen, Wendlingweg 2, 52074 Aachen, Germany, Institut für Biochemie, Medizinische Fakultät der RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany, the ^¶Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom, and ^||Max-Planck-Institut für Molekulare Genetik, Heubnerweg 6, 14059 Berlin, Germany

A novel method employing filter arrays of a cDNA expression library for the identification of substrates for protein kinases was developed. With this technique, we identified a new member of the cyclin family, cyclin L2, as a substrate of the nuclear protein kinase DYRK1A. Cyclin L2 contains an N-terminal cyclin domain and a C-terminal arginine/serine-rich domain (RS domain), which is a hallmark of many proteins involved in pre-mRNA processing. The gene for cyclin L2 encodes the full-length cyclin L2, which is predominantly expressed in testis, as well as a truncated splicing variant (cyclin L2^S) that lacks the RS domain and is ubiquitously expressed in human tissues. Full-length cyclin L2, but not cyclin L2^S, was associated with the cyclin-dependent kinase PITSLRE. Cyclin L2 interacted with splicing factor 2 in vitro and was co-localized with the splicing factor SC35 in the nuclear speckle compartment. Photobleaching experiments showed that a fusion protein of green fluorescent protein and cyclin L2 in nuclear speckles rapidly exchanged with unbleached molecules in the nucleus, similar to other RS domain-containing proteins. In striking contrast, the closely related green fluorescent protein-cyclin L1 was immobile in the speckle compartment. DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. These data characterize cyclin L2 as a highly mobile component of nuclear speckles and suggest that DYRK1A may regulate splicing by phosphorylation of cyclin L2.

Received for publication, October 1, 2003 , and in revised form, November 14, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Be 1967/1-3 and SFB542. 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.

^** To whom correspondence should be addressed: Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der RWTH Aachen, Wendlingweg 2, 52074 Aachen, Germany. Tel.: 49-241-8089136; Fax: 49-241-8082433; E-mail: walter.becker{at}post.rwth-aachen.de.

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