Lysophosphatidic acid induces early growth response-1 (Egr-1) protein expression via protein kinase Cdelta-regulated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation in vascular smooth muscle cells
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 PKCdelta and PKCtheta. Overexpression of dominant-negative PKCdelta, but not dominant-negative PKCtheta, 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 PKCdelta-mediated ERK and JNK activation. This study provides the first evidence that PKCdelta 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.
|ISBN||1083-351X (Electronic) 0021-9258 (Linking)|
|Authors||Iyoda, T.; Zhang, F.; Sun, L.; Hao, F.; Schmitz-Peiffer, C.; Xu, X.; Cui, M. Z.;|
|Publisher Name||JOURNAL OF BIOLOGICAL CHEMISTRY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22577133|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11594|