HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maki, K. Articles by Ikuta, K. Search for Related Content PubMed PubMed Citation Articles by Maki, K. Articles by Ikuta, K.

MEK1/2 Induces STAT5-Mediated Germline Transcription of the TCR Locus in Response to IL-7R Signaling¹

Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan

The IL-7R plays an essential role in T cell development by inducing V-J recombination of the TCR locus through STAT5. Although tyrosine residues in the intracellular domain of the mouse IL-7R -chain (IL-7R) have been implicated in STAT5 activation, it is still unknown whether they are essential for T cell development. In this study, we showed that those IL-7R tyrosine residues are not essential for T cell development, because phenylalanine replacement of four intracellular tyrosine residues (IL-7R-FFFF) partially rescued T cell development of IL-7R^–/– progenitors. To examine signaling pathways activated by IL-7R-FFFF, we introduced a chimeric receptor consisting of the human IL-4R -chain and mouse IL-7R-FFFF (4R/7R-FFFF) into an IL-7-dependent pre-B cell line and found that 4R/7R-FFFF induced TCR germline transcription and STAT5 activation. Treatment of cells with MEK1/2 inhibitors significantly decreased levels of TCR germline transcription and STAT5 tyrosine phosphorylation mediated by 4R/7R-FFFF, suggesting that MEK1/2 plays an alternative role in STAT5 activation by IL-7R. MEK1/2 associated with STAT5 and induced STAT5 tyrosine phosphorylation and DNA binding activity. Furthermore, MEK1 directly phosphorylated a STAT5 tyrosine residue in vitro. Finally, active MEK1 partially rescued TCR germline transcription by IL-7R in a pre-T cell line. These results demonstrate that MEK1/2 induces TCR germline transcription by phosphorylating STAT5 through IL-7R-FFFF and suggest a potential role for MAPK in IL-7R tyrosine-independent activation of STAT5.

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 was supported by Grants-In-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by grants provided by Takeda Science Foundation, Naito Foundation, Sapporo Bioscience Foundation, Astellas Foundation for Research on Metabolic Disorders, and Sumitomo Foundation.

² Address correspondence and reprint requests to Dr. Koichi Ikuta, Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address: ikuta{at}virus.kyoto-u.ac.jp

³ Abbreviations used in this paper: IL-7R, IL-7R -chain; CA, constitutively active; DN, dominant negative; FFFF, four intracellular domain tyrosine residues replaced with four phenylalanine residues; FTOC, fetal thymic organ culture; HA, hemagglutinin; HD, hanging drop; hIL-4, human IL-4; IL-4R, IL-4R -chain; IL-7R-311, IL-7R cDNA with aa residues 312–459 deleted; IL-7R-328, IL-7R cDNA with aa residues 329–459 deleted; 4R/7R, chimeric human IL-4R and mouse IL-7R; WT, wild type.