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Dual Role of the Jak1 FERM and Kinase Domains in Cytokine Receptor Binding and in Stimulation-Dependent Jak Activation¹

Serge Haan^*,, Christiane Margue^*, Arnaud Engrand^*, Catherine Rolvering^*, Hildegard Schmitz-Van de Leur, Peter C. Heinrich, Iris Behrmann^* and Claude Haan^2,*

^* Life Science Research Unit, Faculté des Sciences, de la Technologie et de la Communication, Université du Luxembourg, Luxembourg; and Institut für Biochemie, Uniklinik Aachen, Aachen, Germany

Jak1 is a tyrosine kinase that noncovalently forms tight complexes with a variety of cytokine receptors and is critically involved in signal transduction via cytokines. Jaks are predicted to have a 4.1, ezrin, radixin, moesin (FERM) domain at their N terminus. FERM domains are composed of three structurally unrelated subdomains (F1, F2, and F3) which are in close contact to one another and form the clover-shaped FERM domain. We generated a model structure of the Jak1 FERM domain, based on solved FERM structures and the alignments with other FERM domains. To destabilize different subdomains and to uncover their exact function, we mutated specific hydrophobic residues conserved in FERM domains and involved in hydrophobic core interactions. In this study, we show that the structural integrity of the F2 subdomain of the FERM domain of Jak1 is necessary to bind the IFN-R. By mutagenesis of hydrophobic residues in the hydrophobic core between the three FERM subdomains, we find that the structural context of the FERM domain is necessary for the inhibition of Jak1 phosphorylation. Thus, FERM domain mutations can have repercussions on Jak1 function. Interestingly, a mutation in the kinase domain (Jak1-K907E), known to abolish the catalytic activity, also leads to an impaired binding to the IFN-R when this mutant is expressed at endogenous levels in U4C cells. Our data show that the structural integrity of both the FERM domain and of the kinase domain is essential for both receptor binding and catalytic function/autoinhibition.

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 This work was supported by the Sonderforschungsbereich 542, Teilprojekt B1, and by Université du Luxembourg Grant R1F105L01.

² Address correspondence and reprint requests to Dr. Claude Haan, Life Science Research Unit, Faculté des Sciences, de la Technologie et de la Communication, Université du Luxembourg, 162A, avenue de la Faïencerie, L-1511 Luxembourg. E-mail address: claude.haan{at}uni.lu

³ Abbreviations used in this paper: SH2, Src homology 2; JH, Jak homology; FAK, focal adhesion kinase; OSM, oncostatin M; IRF, IFN regulatory factor; MHC-I, MHC class I; WT, wild type; PIC, polyinosinic-polycytidylic acid; LRP, lung resistance protein.

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