Rho and p38 MAP kinase signaling pathways mediate LPA-stimulated hepatic myofibroblast migration.
Although hepatic myofibroblast migration plays a key role in the liver's injury response, the signal transduction pathways mediating the migration of this cell type are uncertain. Recently, we reported that lysophosphatidic acid (LPA) stimulates the migration of hepatic myofibroblasts. The goal of this study was to test the hypothesis that rho and p38 MAP kinase signaling pathways mediate LPA-stimulated hepatic myofibroblast migration. We measured migration, myosin regulatory light chain and p38 MAP kinase phosphorylation, and contractile force generation by human hepatic myofibroblasts. LPA stimulated migration in a dose-dependent and saturable manner that was partially blocked by Y-27632, a rho-associated kinase inhibitor, as well as by SB-202190, a p38 MAP kinase inhibitor. LPA also induced myosin regulatory light chain phosphorylation and contractile force generation in a Y-27632 dependent, and SB-202190 independent fashion. Moreover, LPA stimulated a dose-dependent and saturable phosphorylation of p38 MAP kinase, which was not altered by Y-27632 or C3 transferase, a rho inactivator. These novel results suggest that LPA stimulates hepatic myofibroblast migration via distinct pathways that signal through rho and p38 MAP kinase.
Tangkijvanich
Pisit
P
Departments of Medicine and Physiology, and CURE Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Melton
Andrew C
AC
Santiskulvong
Chintda
C
Yee
Hal F
HF
D000577:Amides / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008099:Liver / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D011725:Pyridines / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000577:Amides; D007093:Imidazoles; D008246:Lysophospholipids; D011725:Pyridines; C108830:Y 27632; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole