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J. Biol. Chem., Vol. 279, Issue 34, 35486-35493, August 20, 2004

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Janus Kinase (Jak) Subcellular Localization Revisited

THE EXCLUSIVE MEMBRANE LOCALIZATION OF ENDOGENOUS JANUS KINASE 1 BY CYTOKINE RECEPTOR INTERACTION UNCOVERS THE Jak·RECEPTOR COMPLEX TO BE EQUIVALENT TO A RECEPTOR TYROSINE KINASE^*

Iris Behrmann¶, Tanja Smyczek¶, Peter C. Heinrich¶, Hildegard Schmitz-Van de Leur¶, Waraporn Komyod¶, Bernd Giese¶, Gerhard Müller-Newen¶, Serge Haan¶, and Claude Haan¶||

From the ^¶Institut für Biochemie, Universitätsklinikum 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 Janus kinases are considered to be cytoplasmic kinases that constitutively associate with the cytoplasmic region of cytokine receptors, and the Janus kinases (Jaks) are crucial for cytokine signal transduction. We investigated Jak1 localization using subcellular fractionation techniques and fluorescence microscopy (immunofluorescence and yellow fluorescent protein-tagged Jaks). In the different experimental approaches we found Jak1 (as well as Jak2 and Tyk2) predominantly located at membranes. In contrast to previous reports we did not observe Jak proteins in significant amounts within the nucleus or in the cytoplasm. The cytoplasmic localization observed for the Jak1 mutant L80A/Y81A, which is unable to associate with cytokine receptors, indicates that Jak1 does not have a strong intrinsic membrane binding potential and that only receptor binding is crucial for the membrane recruitment. Finally we show that Jak1 remains a membrane-localized protein after cytokine stimulation. These data strongly support the hypothesis that cytokine receptor·Janus kinase complexes can be regarded as receptor tyrosine kinases.

Received for publication, April 15, 2004

Note Added in Proof—As opposed to human Tyk2, the murine orthologue is excluded from the nucleus, as seen by immunofluorescence (S. Pellegrini, personal communication).

^* This work was supported by the Fonds der Chemischen Industrie and by the Deutsche Forschungsgemeinschaft (SFB 542). 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.

To whom correspondence may be addressed. Tel.: 352-466644-361; Fax: 352-466644303; E-mail: Iris.behrmann{at}univ.lu. || To whom correspondence may be addressed. Tel.: 49-241-80-88869; Fax: 49-241-80-82428; E-mail: claude.haan{at}rwth-aachen.de or claude.haan{at}crpsante.healthnet.lu.

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