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p38 MAP kinase mediates platelet‐derived growth factor‐stimulated migration of hepatic myofibroblasts
Author(s) -
Tangkijvanich Pisit,
Santiskulvong Chintda,
Melton Andrew C.,
Rozengurt Enrique,
Yee, Hal F.
Publication year - 2002
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10112
Subject(s) - platelet derived growth factor receptor , membrane ruffling , microbiology and biotechnology , mapk/erk pathway , platelet derived growth factor , biology , kinase , signal transduction , map kinase kinase kinase , focal adhesion , growth factor , biochemistry , receptor , cytoskeleton , cell
Although the migration of hepatic myofibroblasts (HMFs) contributes to the development of fibrosis, the signals regulating migration of these cells are poorly understood. In this study, we tested the hypothesis that HMF migration is stimulated by platelet‐derived growth factor‐BB (PDGF‐BB) through p38 mitogen‐activated protein (MAP) kinase and extracellular signal‐regulated kinase (ERK) signaling pathways. This hypothesis was addressed by directly visualizing the migration of cultured human HMFs into a wound. PDGF‐BB stimulated membrane ruffling, migration, and proliferation. PDGF‐BB also induced activation of p38 MAP kinase, its downstream effector, heat shock protein (HSP) 27, ERK 1 and ERK 2, and p125 focal adhesion kinase (FAK). Selective antagonism of p38 MAP kinase blocked PDGF‐BB‐stimulated HSP 27 phosphorylation, membrane ruffling, and migration, but did not alter PDGF‐BB‐induced proliferation. Selective antagonism of ERK kinase inhibited PDGF‐BB‐induced ERK phosphorylation and proliferation, but did not affect PDGF‐BB‐stimulated migration. Concentrations of PDGF‐BB that stimulated migration and proliferation did not influence myosin‐dependent contractility. Neither selective inhibition of p38 MAP kinase nor ERKs altered PDGF‐BB‐induced activation of FAK. In conclusion, these results provide novel evidence indicating that (1) HMF migration is stimulated by PDGF‐BB through the regulation of membrane ruffling by a p38 MAP kinase signaling pathway, (2) whereas p38 MAP kinase mediates PDGF‐BB‐stimulated migration, but not proliferation, ERKs mediate PDGF‐induced proliferation, but not migration, and (3) increases in myosin‐dependent contractility are not required for PDGF‐BB‐stimulated migration. © 2002 Wiley‐Liss, Inc.