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J. Biol. Chem., Vol. 283, Issue 27, 18522-18529, July 4, 2008

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The Stat3-activating Tyk2 V678F Mutant Does Not Up-regulate Signaling through the Type I Interferon Receptor but Confers Ligand Hypersensitivity to a Homodimeric Receptor^*

Milica Gakovic¹, Josiane Ragimbeau, Véronique Francois², Stefan N. Constantinescu³, and Sandra Pellegrini⁴

From the Cytokine Signaling Unit, CNRS URA 1961, Institut Pasteur, Paris 75724, France and the Ludwig Institute for Cancer Research, Brussels 1200, Belgium

Tyk2 is a Jak family member involved in cytokine signaling through heterodimeric-type receptors. Here, we analyzed the impact of the Val⁶⁷⁸-to-Phe substitution on Tyk2 functioning. This mutation is homologous to the Jak2 Val⁶¹⁷-to-Phe mutation, implicated in myeloproliferative disorders. We studied ligand-independent and ligand-dependent Jak/Stat signaling in cells expressing Tyk2 V678F. Moreover, the effect of Tyk2 V678F was monitored in the context of the native heterodimeric interferon receptor and in the context of a homodimeric receptor chimera, EpoR/R1, containing the ectodomain of the erythropoietin receptor. We show that Tyk2 V678F has increased catalytic potential in vivo and in vitro and more so when it is anchored to the homodimeric receptor. Tyk2 V678F leads to constitutive Stat3 phosphorylation but has no notable effect on the canonical interferon -induced signaling. However, if anchored to the homodimeric EpoR/R1, the mutant confers to the cell increased sensitivity to erythropoietin. Thus, despite the catalytic gain of function of Tyk2 V678F, the effect on ligand-induced signaling is manifest only when two mutant enzymes are juxtaposed via the homodimeric receptor.

Received for publication, February 21, 2008 , and in revised form, May 1, 2008.

^* This work was supported by grants from the Institut Pasteur, the Association pour la Recherche sur le Cancer (ARC 3158), CNRS, and INSERM. 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 Supported by the Ministère de l'Education Nationale, de la Recherche et de la Technologie and a Pasteur-Weizmann fellowship.

² Supported by the Ministry of Education of Mauritius.

³ Supported by the Fonds de la Recherche Scientifique, Fondation contre le cancer, Atlantic Philantropies/Ludwig Institute for Cancer Research Clinical Discoveries Program.

⁴ To whom correspondence should be addressed: Cytokine Signaling Unit, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, Cedex 15, France. Tel: 331-40613305; Fax: 331-40613204; E-mail: pellegri{at}pasteur.fr.

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