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J. Biol. Chem., Vol. 281, Issue 7, 4024-4034, February 17, 2006

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Three Dileucine-like Motifs within the Interbox1/2 Region of the Human Oncostatin M Receptor Prevent Efficient Surface Expression in the Absence of an Associated Janus Kinase^*

Simone Radtke¹, Angela Jörissen, Hildegard Schmitz-Van de Leur, Peter C. Heinrich, and Iris Behrmann²

From the Institut für Biochemie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany and the Laboratoire de Biologie et Physiologie Intégrée, Faculté des Sciences, de la Technologie, et de la Communication, Université du Luxembourg, 162a avenue de la Faïencerie, 1511 Luxembourg

The oncostatin M receptor (OSMR) is part of receptor complexes for oncostatin M and interleukin-31. Signaling events are triggered by Jaks (Janus kinases) that constitutively bind to membrane-proximal receptor regions. Besides their established role in signaling, Jaks are involved in the regulation of the surface expression of several cytokine receptors. Here, we analyzed the structural requirements within the human OSMR that underlie its limited surface expression in the absence of associated Jaks. We identified three dileucine-like motifs within the Jak-binding region of the OSMR that control receptor surface and overall expression. A receptor mutant in which all three motifs were mutated to alanine displayed markedly increased surface expression. Although the surface half-life of this mutant was increased compared with that of the wild-type receptor, no difference in the internalization rate was detectable, implying that these receptors differ in their post-endocytic fate. The protein stability of the wild-type receptor was markedly lower than that of mutant receptors, but could be strongly increased in the presence of the lysosomal inhibitor chloroquine. Our data are consistent with the dileucine motifs being involved in destabilization of receptors devoid of associated Jaks as part of a quality control ensuring signaling competence of OSMRs.

Received for publication, November 1, 2005

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 542 and by the Fonds der Chemischen Industrie, Frankfurt, Germany. 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 Present address: Protein Phosphorylation Lab., Cancer Research UK London Research Inst., London WC2A 3PX, UK.

² To whom correspondence should be addressed: Lab. de Biologie et Physiologie Intégrée, Faculté des Sciences, de la Technologie, and de la Communication, Université du Luxembourg, 162A Avenue de la Faïencerie, 1511 Luxemburg. Tel.: 352-466-644-6740; Fax: 352-466-644-6435; E-mail: iris.behrmann{at}uni.lu.

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