Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 2010 Mar 12;285(11):7911-8. doi: 10.1074/jbc.M109.051219. Epub 2010 Jan 12.
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.
MEKK3 作为一个关键的中间信号分子，在溶血磷脂酸介导的核因子-κB（NF-κB）激活中发挥作用。然而，MEKK3 在分子水平上的激活的精确调控机制尚不完全清楚。在这里，我们报告了在激酶激活环内的 Thr-516 和 Ser-520 两个调节性磷酸化位点的鉴定，这两个位点对于 MEKK3 介导的 IkappaB 激酶β（IKKβ）/NF-κB 激活是必需的。用丙氨酸取代这两个残基，会使 MEKK3 丧失激活 IKKβ/NF-κB 的能力，而用酸性残基取代则使 MEKK3 组成性激活。此外，用丙氨酸取代这两个残基，会使 MEKK3 丧失介导溶血磷脂酸诱导的最佳 IKKβ/NF-κB 激活的能力。
