title: 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.
abstract: 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.
authors.affiliation: Texas Children's Cancer Center Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Xishan
authors.initials: X
authors.lastname: Wang
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
authors.forename: Guiyin
authors.initials: G
authors.lastname: Zhang
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry
chemical_list: D008246:Lysophospholipids; D016328:NF-kappa B; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D013912:Threonine; D012694:Serine; D051550:I-kappa B Kinase; D048748:MAP Kinase Kinase Kinase 3; D054648:Protein Phosphatase 2; C032881:lysophosphatidic acid
references.citation: Nature. 1998 Sep 17;395(6699):297-300
references.pmid: 9751060
references.citation: Genes Dev. 1993 Nov;7(11):2064-70
references.pmid: 8224838
references.citation: J Biol Chem. 2006 Mar 10;281(10):6236-45
references.pmid: 16407301
references.citation: J Biol Chem. 2007 Jan 26;282(4):2473-82
references.pmid: 17121863
references.citation: J Biol Chem. 1999 Jan 8;274(2):687-92
references.pmid: 9873003
references.citation: J Biol Chem. 2010 Mar 12;285(11):7911-8
references.pmid: 20068038
references.citation: Mol Cell Biol. 2002 Mar;22(5):1352-9
references.pmid: 11839802
references.citation: Annu Rev Immunol. 2000;18:621-63
references.pmid: 10837071
references.citation: J Biol Chem. 2002 Oct 18;277(42):40148-55
references.pmid: 12171932
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17085-90
references.pmid: 18952848
references.citation: Cell Signal. 2009 Oct;21(10):1488-94
references.pmid: 19465115
references.citation: EMBO J. 2006 Jan 11;25(1):97-107
references.pmid: 16362041
references.citation: Curr Opin Cell Biol. 2005 Apr;17(2):197-202
references.pmid: 15780597
references.citation: Curr Biol. 2003 Aug 19;13(16):1356-64
references.pmid: 12932319
references.citation: Genes Dev. 2007 Apr 15;21(8):984-96
references.pmid: 17438001
references.citation: Science. 1997 Oct 31;278(5339):866-9
references.pmid: 9346485
references.citation: J Leukoc Biol. 2001 Dec;70(6):839-48
references.pmid: 11739545
references.citation: Science. 1998 Aug 28;281(5381):1360-3
references.pmid: 9721103
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2204-12
references.pmid: 14962831
references.citation: Arch Biochem Biophys. 2002 Nov 1;407(1):103-16
references.pmid: 12392720
references.citation: Mol Cell Biol. 1999 Jul;19(7):4684-94
references.pmid: 10373517
references.citation: Cell. 1998 Jun 26;93(7):1231-40
references.pmid: 9657155
references.citation: Science. 1999 Apr 9;284(5412):309-13
references.pmid: 10195894
references.citation: J Cell Physiol. 2003 Mar;194(3):349-55
references.pmid: 12548554
references.citation: PLoS One. 2008;3(10):e3447
references.pmid: 18927618
references.citation: Science. 1997 May 9;276(5314):952-5
references.pmid: 9139659
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):134-8
references.pmid: 17095601
references.citation: Genes Dev. 1995 Nov 15;9(22):2723-35
references.pmid: 7590248
references.citation: J Biol Chem. 2009 Aug 7;284(32):21201-8
references.pmid: 19458393
references.citation: EMBO J. 1998 Dec 15;17(24):7294-303
references.pmid: 9857186
references.citation: Nature. 1997 Aug 7;388(6642):548-54
references.pmid: 9252186
references.citation: J Biol Chem. 2008 Dec 12;283(50):34994-5002
references.pmid: 18852266
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):145-50
references.pmid: 17179215
references.citation: Cell. 1997 Jul 25;90(2):373-83
references.pmid: 9244310
references.citation: Methods Enzymol. 2003;366:135-44
references.pmid: 14674246
references.citation: Science. 1997 Oct 31;278(5339):860-6
references.pmid: 9346484
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):139-44
references.pmid: 17101977
references.citation: Science. 1998 May 22;280(5367):1258-61
references.pmid: 9596578
references.citation: Cell. 2002 Apr;109 Suppl:S81-96
references.pmid: 11983155
references.citation: Oncogene. 2007 Aug 2;26(35):5145-53
references.pmid: 17297438
references.citation: Nat Immunol. 2001 Jul;2(7):620-4
references.pmid: 11429546
references.citation: Cell. 1997 Oct 17;91(2):243-52
references.pmid: 9346241
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5699-704
references.pmid: 8650155
references.citation: Cell Signal. 2009 Jan;21(1):95-102
references.pmid: 18930133
references.citation: Nat Rev Immunol. 2002 Oct;2(10):725-34
references.pmid: 12360211
references.citation: Annu Rev Immunol. 1996;14:649-83
references.pmid: 8717528
references.citation: Immunol Today. 1998 Feb;19(2):80-8
references.pmid: 9509763
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4438-42
references.pmid: 10200280