title: Lysophosphatidic acid induces early growth response-1 (Egr-1) protein expression via protein kinase Cδ-regulated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation in vascular smooth muscle cells.
abstract: Lysophosphatidic acid (LPA) modulates vascular cell function in vitro and in vivo via regulating the expression of specific genes. Previously, we reported that a transcriptional mechanism controls LPA-induced expression of Egr-1 in vascular smooth muscle cells. Egr-1 is a master transcription factor mediating the expression of various genes that have been implied to modulate a broad spectrum of vascular pathologies. In this study, we determined the essential intracellular signaling pathway leading to LPA-induced Egr-1 expression. Our data demonstrate that activation of ERK1/2 and JNK, but not p38 MAPK, is required for LPA-induced Egr-1 expression in smooth muscle cells. We provide the first evidence that MEK-mediated JNK activation leads to LPA-induced gene expression. JNK2 is required for Egr-1 induction. Examining the upstream kinases that mediate ERK and JNK activation, leading to Egr-1 expression, we found that LPA-induced activation of MAPKs and expression of Egr-1 are dependent on PKC activation. We observed that LPA rapidly activates PKCδ and PKCθ. Overexpression of dominant-negative PKCδ, but not dominant-negative PKCθ, diminished activation of ERK and JNK and blocked LPA-induced expression of Egr-1 mRNA and protein. We also evaluated LPA receptor involvement. Our data reveal an intracellular regulatory mechanism: LPA induction of Egr-1 expression is via LPA cognate receptor (LPA receptor 1)-dependent and PKCδ-mediated ERK and JNK activation. This study provides the first evidence that PKCδ mediates ERK and JNK activation in the LPA signaling pathway and that this pathway is required for LPA-induced gene regulation as evidenced by Egr-1 expression.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iyoda
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Zhang
authors.forename: Longsheng
authors.initials: L
authors.lastname: Sun
authors.forename: Feng
authors.initials: F
authors.lastname: Hao
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmitz-Peiffer
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D007527:Isoenzymes; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D048056:Mitogen-Activated Protein Kinase 9; D051745:Protein Kinase C-delta; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; C032881:lysophosphatidic acid