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J. Biol. Chem., Vol. 280, Issue 27, 25760-25768, July 8, 2005

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The Jak1 SH2 Domain Does Not Fulfill a Classical SH2 Function in Jak/STAT Signaling but Plays a Structural Role for Receptor Interaction and Up-regulation of Receptor Surface Expression^*

Simone Radtke, Serge Haan¶, Angela Jörissen, Heike M. Hermanns, Sandra Diefenbach, Tanya Smyczek, Hildegard Schmitz-VandeLeur, Peter C. Heinrich, Iris Behrmann||, and Claude Haan||**

From the Institut für Biochemie, Uniklinik 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, L-1511 Luxembourg

The presence of a Src homology 2 (SH2) domain sequence similarity in the sequence of Janus kinases (Jaks) has been discussed since the first descriptions of these enzymes. We performed an in depth study to determine the function of the Jak1 SH2 domain. We investigated the functionality of the Jak1 SH2 domain by stably reconstituting Jak1-defective human fibrosarcoma cells U4C with endogenous amounts of Jak1 in which the crucial arginine residue Arg⁴⁶⁶ within the SH2 domain has been replaced by lysine. This mutant still binds to the receptor subunits gp130 and OSMR. Moreover, the SH2 R466K mutation does not affect the subcellular distribution of Jak1 as assessed by cell fractionation and confocal microscopy of cells expressing endogenous levels of non-tagged or a yellow fluorescent protein (YFP)-tagged Jak1-R466K, respectively. Likewise, the signaling capacity of Jak1 was not affected by this point mutation. However, we found that the SH2 domain is structurally important for cytokine receptor binding and surface expression of the OSMR.

Received for publication, January 24, 2005 , and in revised form, May 12, 2005.

^* This work was supported by grants from the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft (SFB 542; HA 3433/1-1). 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. 1 and 2.

These authors contributed equally to this work.

¶ To whom correspondence may be addressed. Tel.: 49-241-8088414; Fax: 49-241-8082428; E-mail: serge.haan{at}rwth-aachen.de. ^** To whom correspondence may be addressed. Tel.: 352-466644-361; Fax: 352-466644-435; E-mail: claude.haan{at}uni.lu.

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