Abstract
Lysophosphatidic acid (LPA) is a potent agonist that exerts various cellular functions on many cell types through binding to its cognate G protein-coupled receptors (GPCRs). Although LPA induces NF-kappaB activation by acting on its GPCR receptor, the molecular mechanism of LPA receptor-mediated NF-kappaB activation remains to be well defined. In the present study, by using MEKK3-, TAK1-, and IKKbeta-deficient murine embryonic fibroblasts (MEFs), we found that MEKK3 but not TAK1 deficiency impairs LPA and protein kinase C (PKC)-induced IkappaB kinase (IKK)-NF-kappaB activation, and IKKbeta is required for PKC-induced NF-kappaB activation. In addition, we demonstrate that LPA and PKC-induced IL-6 and MIP-2 production are abolished in the absence of MEKK3 but not TAK1. Together, our results provide the genetic evidence that MEKK3 but not TAK1 is required for LPA receptor-mediated IKK-NF-kappaB activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chemokine CXCL2 / metabolism
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Fibroblasts / enzymology
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Fibroblasts / metabolism
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Gene Knockdown Techniques
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I-kappa B Kinase / deficiency
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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Interleukin-6 / metabolism
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Lysophospholipids / pharmacology*
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MAP Kinase Kinase Kinase 3 / deficiency
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MAP Kinase Kinase Kinase 3 / genetics
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MAP Kinase Kinase Kinase 3 / metabolism*
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MAP Kinase Kinase Kinases / deficiency
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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NF-kappa B / metabolism*
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Protein Kinase C / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
Substances
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Chemokine CXCL2
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Interleukin-6
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Lysophospholipids
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NF-kappa B
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Receptors, G-Protein-Coupled
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I-kappa B Kinase
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Protein Kinase C
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MAP Kinase Kinase Kinase 3
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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lysophosphatidic acid