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J Biol Chem. 2010 Mar 12;285(11):7911-8. doi: 10.1074/jbc.M109.051219. Epub 2010 Jan 12.

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.

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Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.


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.

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