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Published Online September 9, 2004
Science DOI: 10.1126/science.1099414

Reports

Submitted on April 21, 2004
Accepted on August 18, 2004

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

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

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 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; 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.

* To whom correspondence should be addressed.
Michael Karin , E-mail: karinoffice{at}ucsd.edu

{dagger}Present address: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.

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

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 find that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase via its phosphorylation. Activation of the JNK mitogen-activated protein (MAP) 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.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)