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J. Biol. Chem., Vol. 283, Issue 28, 19465-19477, July 11, 2008

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Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation^*

Christoph Hintzen, Christina Evers, Barbara E. Lippok, Rudolf Volkmer, Peter C. Heinrich, Simone Radtke¹², and Heike M. Hermanns¹³

From the Institut für Biochemie, Universitätsklinikum RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany and the Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Schumannstrasse 20-21, 10117 Berlin, Germany

Human and murine oncostatin M (OSM) induce their bioactivities through a heterodimeric receptor complex consisting of gp130 and the OSM receptor (OSMR), which initiates a signaling pathway involving Janus kinases (JAKs) and transcription factors of the signal transducers and activators of transcription (STAT) family. In contrast to the signal transducing receptor subunit gp130, the OSMR allows strong activation of STAT5B. The underlying molecular mechanism, however, remained unclear. Here we demonstrate that the human and murine OSM receptors use distinct mechanisms for STAT5B activation. The human receptor contains a STAT5B recruiting tyrosine motif (Tyr⁸³⁷/Tyr⁸³⁹) C-terminal to the box 1/2 region, which is absent in the mouse receptor. In contrast, the murine receptor initiates STAT5 activation directly via the receptor bound Janus kinases. Intriguingly, the murine receptor preferentially recruits JAK2, whereas the human receptor seems to have a higher affinity for JAK1. We identify a single amino acid (Phe⁸²⁰) in the human receptor that is responsible for this preference. Exchange by the murine counterpart (Cys⁸¹⁵) allows recruitment of JAK2 by the human receptor and consequently activation of STAT5B independently of receptor tyrosine motifs. STAT5B interacts directly with JAK2 only in response to activation of the murine OSMR or the mutated human OSMR. Additionally, we show that OSM-induced STAT1 phosphorylation occurs independently of receptor tyrosine motifs and is mediated directly by Janus kinases, whereas the two C-terminally located tyrosine residues Tyr⁹¹⁷/Tyr⁹⁴⁵ of the OSMR are crucial for STAT3 activation.

Received for publication, December 13, 2007 , and in revised form, April 3, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 542, TP B6 (to H. M. H.), and SFB 449 (to R. V.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² Present address: Cancer Research UK, London Research Institute, Protein Phosphorylation Laboratory, London WC2A3PX, UK.

³ To whom correspondence should be addressed. Present address: Rudolf-Virchow-Zentrum, Universität Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany. Tel.: 49-931-201-48722; Fax: 49-931-201-48702; E-mail: heike.hermanns{at}virchow.uni-wuerzburg.de.

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