title: Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.
abstract: Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Accumulation of PSCs is a fundamental feature of pancreatic fibrosis, and platelet-derived growth factor (PDGF)-BB is the most potent mitogen for PSCs. But, the molecular mechanisms responsible for PDGF's actions in PSCs are largely unknown. In hepatic stellate cells, it has been established that activation of both phosphatidylinositol (PI) 3-kinase and extracellular-signal regulated kinase (ERK) pathways is required for PDGF-BB-induced proliferation and migration. The aim of this study was to elucidate the signaling pathways mediating PDGF-BB's actions in PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. Culture-activated PSCs expressed PDGF alpha- and beta-receptors. PDGF-BB induced autophosphorylation of its receptor, followed by the activation of PI 3-kinase, Akt, and ERK pathways. Activation of PI 3-kinase was not required for PDGF-BB-induced ERK activation. PDGF-BB induced approximately five-fold increase in proliferation and chemotaxis of PSCs. Inhibition of ERK pathway with PD98059 completely blocked proliferation, whereas PD98059 had a modest inhibitory effect on cell migration (approximately 50%). On the other hand, inhibition of PI 3-kinase pathway with wortmannin or LY294002 almost completely inhibited migration, but did not affect proliferation of PSCs. In conclusion, our results suggest that ERK pathway regulates proliferation and migration in response to PDGF-BB, whereas PI 3-kinase mediates cellular migration, but not proliferation of PSCs.
authors.affiliation: Pancreas Research Group, Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. amasamune@int3.med.tohoku.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satoh
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kume
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002455:Cell Division; D002465:Cell Movement; D002633:Chemotaxis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one