ERK5 is involved in TCR-induced apoptosis through the modification of Nur77.
Nur77 is a nuclear orphan steroid receptor that has been implicated in negative selection when immature T cells are strongly activated through interaction with self peptide-MHC complexes. The expression of Nur77 in thymocytes and T cell lines leads to apoptosis in a manner dependent on its transcriptional activity. It is well established that Nur77 function is negatively regulated by post-translational modification. Here we demonstrate that the MAPK-induced phosphorylation of Nur77 during T cell activation plays a critical role in the induction of apoptosis. Upon T cell receptor (TCR) stimulation, ERK5 (also known as big MAP kinase 1, BMK1), a member of the MAPK family, phosphorylates Nur77, leading to its transcriptional activation. In contrast, the activation of the ERK2 signaling pathway failed to activate Nur77 although ERK2 is also able to phosphorylate Nur77. Furthermore, the blockade of ERK5 signaling pathway suppressed TCR-induced cell death. These results indicate that ERK5 regulates Nur77 function through its phosphorylation.
Fujii
Yasushi
Y
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Matsuda
Satoshi
S
Takayama
Gensuke
G
Koyasu
Shigeo
S
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7