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J. Biol. Chem., Vol. 281, Issue 13, 8458-8468, March 31, 2006

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Oncostatin M Receptor-mediated Signal Transduction Is Negatively Regulated by SOCS3 through a Receptor Tyrosine-independent Mechanism^*

Claudia Stross, Simone Radtke¹, Thomas Clahsen, Christa Gerlach, Rudolf Volkmer-Engert, Fred Schaper, Peter C. Heinrich, and Heike M. Hermanns²

From the Institut für Biochemie, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany and Institut für Medizinische Immunologie, Campus Mitte, Charité-Universitätsmedizin Berlin, Schumannstrasse 20–21, 10117 Berlin, Germany

Down-regulation of interleukin (IL)-6-type cytokine signaling has been shown to occur, among other mechanisms, via induction of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3). Binding of SOCS3 to the phosphorylated Tyr⁷⁵⁹ in the cytoplasmic region of gp130, the common signal transducing receptor chain of all IL-6-type cytokines, is necessary for inhibition of Janus kinase-mediated signaling. In the present study, we analyzed the effect of SOCS3 on signal transduction by the proinflammatory cytokine oncostatin M (OSM), which signals through a receptor complex of gp130 and the OSM receptor (OSMR). OSM leads to a much stronger and prolonged induction of SOCS3 in HepG2 hepatoma cells and murine embryonal fibroblasts (MEF) compared with IL-6. A negative effect of SOCS3 on OSM signaling was confirmed using MEF cells lacking SOCS3. We can show that the OSMR-mediated signaling is inhibited by SOCS3 to a similar extent as previously described for gp130. However, the inhibition occurs independent of tyrosine motifs within the OSMR. Instead, SOCS3 interacts directly with JAK1 in a stimulation-dependent manner, a mechanism so far only known for SOCS1.

Received for publication, October 14, 2005 , and in revised form, December 29, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft (Bonn, Germany) Grant SFB 542, TP B6, and by the Fonds der Chemischen Industrie (Frankfurt a.M., 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 Laboratory, Cancer Research UK, London Research Institute, London, UK.

² To whom correspondence should be addressed. Tel.: 49-241-8088868; Fax: 49-241-8082428; E-mail: hermanns{at}rwth-aachen.de.

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