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J. Biol. Chem., Vol. 279, Issue 34, 36112-36120, August 20, 2004

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Characterization of the Signaling Capacities of the Novel gp130-like Cytokine Receptor^*

Alexandra Dreuw, Simone Radtke, Stefan Pflanz, Barbara E. Lippok, Peter C. Heinrich, and Heike M. Hermanns¶

From the Institut für Biochemie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany

The gp130-like receptor (GPL) is a recently cloned member of the family of type I cytokine receptors. The name reflects its close relationship to gp130, the common receptor subunit of the interleukin (IL)-6-type cytokines. Indeed, the recently proposed ligand for GPL, IL-31, is closely related to the IL-6-type cytokines oncostatin M, leukemia inhibitory factor, and cardiotrophin-1. The second signal transducing receptor for IL-31 seems to be the oncostatin M receptor (OSMR). The present study characterizes in depth the molecular mechanisms underlying GPL-mediated signal transduction. GPL is a strong activator of STAT3 and STAT5, whereas STAT1 is only marginally tyrosine-phosphorylated. We identify tyrosine residues 652 and 721 in the cytoplasmic region of the longest isoform of GPL (GPL₇₄₅) as the major STAT5- and STAT3-activating sites, respectively. Additionally, we demonstrate Jak1 binding to GPL and its activation in heteromeric complexes with the OSMR but also in a homomeric receptor complex. Most interesting, unlike OSMR and gp130, GPL is insufficient to mediate ERK1/2 phosphorylation. We propose that this is due to a lack of recruitment of the tyrosine phosphatase SHP-2 or the adaptor protein Shc to the cytoplasmic domain of GPL.

Received for publication, February 2, 2004 , and in revised form, June 1, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 542 (Bonn, Germany) 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.

Present address: Micromet AG, Staffelseestrasse 2, 81477 München, Germany.

To whom correspondence may be addressed. Tel.: 49-241-8088831; Fax: 49-241-8082428; E-mail: heinrich{at}rwth-aachen.de. ¶ To whom correspondence may be addressed. Tel.: 49-241-8088868; Fax: 49-241-8082428; E-mail: hermanns{at}rwth-aachen.de.

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