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

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.