MEKK3 is required for lysophosphatidic acid-induced NF-kappaB activation.
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.
Sun
Wenjing
W
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Li
Hongxiu
H
Yu
Yang
Y
Fan
Yihui
Y
Grabiner
Brian C
BC
Mao
Renfang
R
Ge
Ningling
N
Zhang
Hong
H
Fu
Songbin
S
Lin
Xin
X
Yang
Jianhua
J
D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D048748:MAP Kinase Kinase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
D054426:Chemokine CXCL2; D051550:I-kappa B Kinase; D015850:Interleukin-6; D008246:Lysophospholipids; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011493:Protein Kinase C; D043562:Receptors, G-Protein-Coupled; D000099151:MAP Kinase Kinase Kinase 7; C032881:lysophosphatidic acid