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Science 306 (5694): 271-275

Copyright © 2004 by the American Association for the Advancement of Science

Jun Turnover Is Controlled Through JNK-Dependent Phosphorylation of the E3 Ligase Itch

Min Gao,1 Tord Labuda,1,2 Ying Xia,1* Ewen Gallagher,1 Deyu Fang,3{dagger} Yun-Cai Liu,3 Michael Karin1{ddagger}

Abstract: The turnover of Jun proteins, like that of other transcription factors, is regulated through ubiquitin-dependent proteolysis. Usually, such processes are regulated by extracellular stimuli through phosphorylation of the target protein, which allows recognition by F box–containing E3 ubiquitin ligases. In the case of c-Jun and JunB, we found that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. This pathway modulates cytokine production by effector T cells.

1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0723, USA.
2 Department of Medical Microbiology and Immunology and Institute of Molecular Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
3 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.

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* Present address: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267–0056, USA.

{dagger} Present address: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109–0606, USA.

{ddagger} To whom correspondence should be addressed: E-mail: karinoffice{at}

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