Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation.
MEKK3 serves as a critical intermediate signaling molecule in lysophosphatidic acid-mediated nuclear factor-kappaB (NF-kappaB) activation. However, the precise regulation for MEKK3 activation at the molecular level is still not fully understood. Here we report the identification of two regulatory phosphorylation sites at Thr-516 and Ser-520 within the kinase activation loop that is essential for MEKK3-mediated IkappaB kinase beta (IKKbeta)/NF-kappaB activation. Substitution of these two residues with alanine abolished the ability of MEKK3 to activate IKKbeta/NF-kappaB, whereas replacement with acidic residues rendered MEKK3 constitutively active. Furthermore, substitution of these two residues with alanine abolished the ability of MEKK3 to mediate lysophosphatidic acid-induced optimal IKKbeta/NF-kappaB activation.
Sun
Wenjing
W
Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Ge
Ningling
N
Yu
Yang
Y
Burlingame
Susan
S
Li
Xiaonan
X
Zhang
Ming
M
Ye
Shenglong
S
Fu
Songbin
S
Yang
Jianhua
J
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000918:Antibody Specificity; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D008246:Lysophospholipids / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D011817:Rabbits; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine / Q000378:metabolism
D000906:Antibodies; C508600:IL6 protein, human; D015850:Interleukin-6; D008246:Lysophospholipids; D016328:NF-kappa B; D013912:Threonine; D012694:Serine; D008156:Luciferases; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human; C032881:lysophosphatidic acid