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J. Biol. Chem., Vol. 280, Issue 33, 29409-29419, August 19, 2005

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Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway^*

Masakatsu Yamashita, Ryo Shinnakasu, Hikari Asou, Motoko Kimura, Akihiro Hasegawa, Kahoko Hashimoto, Naoya Hatano¶, Masato Ogata¶, and Toshinori Nakayama||

From the Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, the Department of Life and Environmental Sciences and High Technology Research Center, Chiba Institute of Technology, Narashino, Tsudanuma, Chiba 275-0016, and the ^¶Department of Biochemistry, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan

Differentiation of naive CD4 T cells into Th2 cells requires protein expression of GATA3. Interleukin-4 induces STAT6 activation and subsequent GATA3 transcription. Little is known, however, on how T cell receptor-mediated signaling regulates GATA3 and Th2 cell differentiation. Here we demonstrated that T cell receptor-mediated activation of the Ras-ERK MAPK cascade stabilizes GATA3 protein in developing Th2 cells through the inhibition of the ubiquitin-proteasome pathway. Mdm2 was associated with GATA3 and induced ubiquitination on GATA3, suggesting its role as a ubiquitin-protein isopeptide ligase for GATA3 ubiquitination. Thus, the Ras-ERK MAPK cascade controls GATA3 protein stability by a post-transcriptional mechanism and facilitates GATA3-mediated chromatin remodeling at Th2 cytokine gene loci leading to successful Th2 cell differentiation.

Received for publication, March 2, 2005 , and in revised form, June 3, 2005.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan), Grants-in-aid for Scientific Research Priority Areas Research 13218016 and 16043211, Scientific Research B 14370107, Scientific Research C 16616003 and 15790248, and Special Coordination Funds for Promoting Science and Technology, the Ministry of Health, Labor, and Welfare (Japan), the Program for Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (Japan), The Japan Health Science Foundation, Uehara Memorial Foundation, and Mochida Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. 1.

^|| To whom correspondence should be addressed: Dept. of Immunology (H3), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670 Japan. Tel.: 81-43-226-2200; Fax: 81-43-227-1498; E-mail: tnakayama{at}faculty.chiba-u.jp.

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