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.
Sun
Wenjing
W
Texas Children's Cancer Center Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Wang
Hao
H
Zhao
Xiumei
X
Yu
Yang
Y
Fan
Yihui
Y
Wang
Hao
H
Wang
Xishan
X
Lu
Xiongbin
X
Zhang
Guiyin
G
Fu
Songbin
S
Yang
Jianhua
J
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
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
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