Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IκB kinase β/nuclear factor-κB activation

Abstract

MEKK3 is a central intermediate signaling component in lysophosphatidic acid (LPA)-induced activation of the nuclear factor-κB (NF-κB). 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) β-isoform results in dephosphorylation of MEKK3 at Thr-516 and Ser-520 and termination of MEKK3-mediated NF-κB 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 IκB kinase β (IKKβ) phosphorylation and NF-κB activation. These data suggest that PP2A plays an important role in the termination of LPA-mediated NF-κB activation through dephosphorylating and inactivating MEKK3. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.