Platelet-derived growth factor-BB and lysophosphatidic acid distinctly regulate hepatic myofibroblast migration through focal adhesion kinase.
Although hepatic myofibroblast (HMF) migration contributes to the development of fibrosis, the mechanisms coordinating this movement are uncertain. We determined the effects of lysophosphatidic acid (LPA) and platelet-derived growth factor-BB (PDGF) on actin polymerization, FAK tyrosine phosphorylation, and migration of cultured human HMFs. LPA (0.4-100 microM) stimulated migration, FAK tyrosine phosphorylation, and stress fiber assembly with a sigmoidal dose response. PDGF (1-250 ng/ml) stimulated migration, FAK tyrosine phosphorylation, and actin polymerization with a bell-shape dose-response characterized by a maximum at 10-25 ng/ml. Concentrations of cytochalasin D, which abolished FAK tyrosine phosphorylation, also blocked LPA- and PDGF-induced migration. A dose of 1-10 ng/ml PDGF acted synergistically with LPA (10 microM) to stimulate FAK tyrosine phosphorylation and migration, whereas higher concentrations of PDGF (100-250 ng/ml) inhibited FAK tyrosine phosphorylation and migration in response to LPA (10 microM). These data indicate that PDGF and LPA coordinately govern the migration of HMFs by differentially regulating FAK and suggest a novel model in which PDGF, acting as an amplifier/attenuator of LPA-induced signaling, facilitates HMF accumulation within injured areas of the liver.
Tangkijvanich
Pisit
P
Department of Medicine, School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Melton
Andrew C
AC
Chitapanarux
Taned
T
Han
Jiu
J
Yee
Hal F
HF
D000199:Actins / Q000378:metabolism; D000077214:Becaplermin; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000201:enzymology; D008246:Lysophospholipids / Q000494:pharmacology*; D009218:Myosins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D015398:Signal Transduction
D000199:Actins; D008246:Lysophospholipids; D019384:Nucleic Acid Synthesis Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D015638:Cytochalasin D; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D009218:Myosins