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MEKK1 Binds HECT E3 Ligase Itch by Its Amino-Terminal RING Motif to Regulate Th2 Cytokine Gene Expression¹

Thomas Enzler^*, Xing Chang, Valeria Facchinetti, Gerry Melino, Michael Karin^¶, Bing Su and Ewen Gallagher^2,||

^* Stanford University School of Medicine, Stanford, CA 94305; Department of Immunology and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 09519; Department of Immunology, M. D. Anderson Cancer Center, Houston, TX 77030; Istituto Dermopatico dell’Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico Biochemistry Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy; ^¶ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093; and ^|| Department of Immunology, Imperial College London, London, United Kingdom

MEKK1-dependent signaling regulates HECT E3 ligase Itch, resulting in elevated catalytic activity. After TCR costimulation, MEKK1 predominantly induces JNK1 activation, whereas the related kinase MEKK2 regulates ERK5 activation. MEKK1 becomes phosphorylated on multiple sites and polyubiquitinated following TCR costimulation. E3 ligase Itch is recruited to activated MEKK1, but not MEKK2, and this novel scaffolding interaction is dependent on MEKK1 Thr¹³⁸¹ phosphorylation within the kinase domain and an intact MEKK1 RING finger motif. MEKK1 phosphorylation on Thr¹³⁸¹ is observed during Th2 differentiation, but not under Th1 differentiation. Both Itch and the MEKK1 kinase domain are important for Il4 and Il6 cytokine gene expression under Th2 conditions.

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 is supported in part by grant AI 063348 (NIH; to B.S.) and starting funds from Imperial College London (to E.G.). X.C. is a recipient of Gershon/Trudeau Fellowship from Immunobiology at Yale University.

² Address correspondence and reprint requests to Dr. Ewen Gallagher, Department of Immunology, Imperial College London, London, United Kingdom. E-mail: e.gallagher{at}imperial.ac.uk

³ Abbreviations used in this paper: MEKK, MEK kinase; PRR, proline-rich region; Ub, ubiquitin; WT, wild type.