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‡∥
- ‡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
- ↵∥ 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.
Abstract
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 March 2, 2005.
- Revision received June 3, 2005.
- The American Society for Biochemistry and Molecular Biology, Inc.
