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A more recent version of this article appeared on November 1, 2002
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Papers In Press, published online ahead of print August 21, 2002
J. Biol. Chem, 10.1074/jbc.M204426200
Submitted on May 7, 2002
Revised on August 21, 2002
Accepted on August 21, 2002

Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low-density lipoprotein-receptor related protein (LRP)

Christina Lutz, Johannes Nimpf, Marcel Jenny, Karl Boecklinger, Christiane Enzinger, Gerd Utermann, Gabriele Baier-Bitterlich, and Gottfried Baier

Med. Biology & Human Genetics, University of Innsbruck, Innsbruck A6020

Corresponding Author: Gottfried.Baier{at}uibk.ac.at

Lipoprotein receptors, such as LRP, have been shown to assemble multiprotein complexes containing intracellular signaling molecules, however in vivo, its signaling function is poorly understood. Using a novel LRP receptor fusion construct, a type I transmembrane protein chimera, termed sIgG-LRP (bearing the intracellular COOH-terminal tail of human LRP as recombinant fusion to a transmembrane region plus the extracellular IgG-Fc domain), we here investigated LRP signal transduction specificity in intact cells. First and similar to activated alpha2-macroglobulin as agonist of endogenous LRP, expression of sIgG-LRP demonstrated significant apoptosis protection. Second and similar to alpha2-macroglobulin-induced endogenous LRP, sIgG-LRP is sufficient to negatively modulate mitogen-induced Elk-1 and cJun (but not NF-kappaB) transcriptional activity. Third, expression of sIgG-LRP also impaired cJun transactivation mediated by constitutive active mutants of Rac-1 and MEKK-1. Fourth and unexpectedly, sIgG-LRP expression was found to be associated with a marked enhancement of mitogen-induced cJun amino-terminal kinase (JNK) activation. Fifth, confocal microscopic examination and subcellular fractionation demonstrated that sIgG-LRP and JNK co-localize in transfected cells. Therefore, sIgG-LRP expression was found to significantly impair activation-induced translocation of JNK into the nucleus. Taken together, we here demonstrate that sIgG-LRP protein sequesters activated JNK into the plasma membrane compartment in intact cells, inhibiting nuclear activation of the JNK-dependent transcription factors Elk-1 and cJun.


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