Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 28, Pages 21341-21348Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.104224
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Funding
- National Institutes of Health/NCI [1R21CA106513-01A2, 5P30CA125123-03]
- National Cancer Institute [RSG-06-070-01-TBE]
- American Cancer Society
- Virginia and L. E. Simmons Family Foundation
- National Natural Science Foundation of China [30771198, 30971583]
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MEKK3 is a central intermediate signaling component in lysophosphatidic acid (LPA)-induced activation of the nuclear factor-kappa B (NF-kappa B). 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-kappa B 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 I kappa B kinase beta (IKK beta) phosphorylation and NF-kappa B activation. These data suggest that PP2A plays an important role in the termination of LPA-mediated NF-kappa B activation through dephosphorylating and inactivating MEKK3.
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