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J. Biol. Chem., Vol. 279, Issue 21, 22404-22411, May 21, 2004

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Insulin-activated Erk-mitogen-activated Protein Kinases Phosphorylate Sterol Regulatory Element-binding Protein-2 at Serine Residues 432 and 455 in Vivo^*

Jorg Kotzka, Stefan Lehr, Gunther Roth, Haluk Avci, Birgit Knebel, and Dirk Muller-Wieland

From the German Diabetes Center at the Heinrich-Heine University Düsseldorf, Institute for Clinical Biochemistry and Pathobiochemistry, D-40225 Düsseldorf, Germany

The transcription factor sterol regulatory element binding protein (SREBP)-2 plays a pivotal role in lipid metabolism. Previously, we have shown that the mature form of SREBP-2 is a substrate of Erk-mitogen-activated protein kinases (MAPK). The aim of the present study was to identify Erk-specific phosphorylation sites. Using a protein chemistry approach, we could identify Ser-432 and Ser-455 as major phosphorylation sites. Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/DNA interaction, but enhances trans-activity. In intact cells, SREBP-2 is phosphorylated by insulin, which seems to be related to their bio-responses on low density lipoprotein receptor activity. These results suggest that activation of Erk-MAPK pathways by hormones such as insulin might be related to a novel regulatory principle of SREBP-2.

Received for publication, February 3, 2004

^* This study was supported by German Ministry of Education and Research Grant BMBF/01 KS 9502. 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: Deutsches Diabetes Zentrum, Institut für Klinische Biochemie und Pathobiochemie, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany. Tel.: 49-211-3382-240; Fax: 49-211-3382-430; E-mail: mueller-wieland{at}ddfi.uni-duesseldorf.de.

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