MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression.
MEKK1-dependent signaling regulates HECT E3 ligase Itch, resulting in elevated catalytic activity. After TCR costimulation, MEKK1 predominantly induces JNK1 activation, whereas the related kinase MEKK2 regulates ERK5 activation. MEKK1 becomes phosphorylated on multiple sites and polyubiquitinated following TCR costimulation. E3 ligase Itch is recruited to activated MEKK1, but not MEKK2, and this novel scaffolding interaction is dependent on MEKK1 Thr(1381) phosphorylation within the kinase domain and an intact MEKK1 RING finger motif. MEKK1 phosphorylation on Thr(1381) is observed during Th2 differentiation, but not under Th1 differentiation. Both Itch and the MEKK1 kinase domain are important for Il4 and Il6 cytokine gene expression under Th2 conditions.
Enzler
Thomas
T
Stanford University School of Medicine, Stanford, CA 94305, USA.
Chang
Xing
X
Facchinetti
Valeria
V
Melino
Gerry
G
Karin
Michael
M
Su
Bing
B
Gallagher
Ewen
E
D000818:Animals; D001665:Binding Sites; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D054829:RING Finger Domains; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018418:Th2 Cells; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4