Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells

Atsushi Masamune, Kazuhiro Kikuta, Masahiro Satoh, Kiyoshi Kume, Tooru Shimosegawa

Research output: Contribution to journalReview articlepeer-review

67 Citations (Scopus)

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 α- and β-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 PI3-kinase mediates cellular migration, but not proliferation of PSCs.

Original languageEnglish
Pages (from-to)69-84
Number of pages16
JournalTohoku Journal of Experimental Medicine
Volume199
Issue number2
DOIs
Publication statusPublished - 2003 Feb 1

Keywords

  • MAP kinase
  • Pancreatic fibrosis
  • Pancreatic stellate cells
  • Phosphatidylinositol 3-kinase
  • Platelet-derived growth factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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