MEK1/2 induces STAT5-mediated germline transcription of the TCRgamma locus in response to IL-7R signaling.
The IL-7R plays an essential role in gammadelta T cell development by inducing V-J recombination of the TCRgamma locus through STAT5. Although tyrosine residues in the intracellular domain of the mouse IL-7R alpha-chain (IL-7Ralpha) have been implicated in STAT5 activation, it is still unknown whether they are essential for gammadelta T cell development. In this study, we showed that those IL-7Ralpha tyrosine residues are not essential for gammadelta T cell development, because phenylalanine replacement of four intracellular tyrosine residues (IL-7R-FFFF) partially rescued gammadelta T cell development of IL-7Ralpha-/- progenitors. To examine signaling pathways activated by IL-7R-FFFF, we introduced a chimeric receptor consisting of the human IL-4R alpha-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 TCRgamma germline transcription and STAT5 activation. Treatment of cells with MEK1/2 inhibitors significantly decreased levels of TCRgamma 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 TCRgamma germline transcription by IL-7R in a pre-T cell line. These results demonstrate that MEK1/2 induces TCRgamma germline transcription by phosphorylating STAT5 through IL-7R-FFFF and suggest a potential role for MAPK in IL-7R tyrosine-independent activation of STAT5.
Maki
Kazushige
K
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Ikuta
Koichi
K
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D010768:Phosphoserine; D019000:Phosphotyrosine; D004247:DNA; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2