Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation.

MEKK3 is a central intermediate signaling component in lysophosphatidic acid (LPA)-induced activation of the nuclear factor-kappaB (NF-kappaB). However, the precise mechanism for the termination of MEKK3 kinase activity is not fully understood. Using a functional genomic approach, we have identified a protein serine/threonine phosphatase, protein phosphatase 2A (PP2A), as a ...
MEKK3 phosphatase. Overexpression of PP2A catalytic subunit (PP2Ac) beta-isoform results in dephosphorylation of MEKK3 at Thr-516 and Ser-520 and termination of MEKK3-mediated NF-kappaB activation. PP2Ac associates with the phosphorylated form of MEKK3 and the interaction between PP2Ac and MEKK3 is induced by LPA in a transient fashion in the cells. Furthermore, knockdown of PP2Ac expression enhances LPA-induced MEKK3-mediated IkappaB kinase beta (IKKbeta) phosphorylation and NF-kappaB activation. These data suggest that PP2A plays an important role in the termination of LPA-mediated NF-kappaB activation through dephosphorylating and inactivating MEKK3.
Mesh Terms:
Cell Line, HeLa Cells, Humans, I-kappa B Kinase, Lysophospholipids, MAP Kinase Kinase Kinase 3, NF-kappa B, Phosphorylation, Protein Isoforms, Protein Phosphatase 2, RNA, Small Interfering, Retroviridae, Serine, Signal Transduction, Threonine
J. Biol. Chem.
Date: Jul. 09, 2010
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