RRC ID 1613
Author Gao Z, Sasaoka T, Fujimori T, Oya T, Ishii Y, Sabit H, Kawaguchi M, Kurotaki Y, Naito M, Wada T, Ishizawa S, Kobayashi M, Nabeshima Y, Sasahara M.
Title Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing.
Journal J. Biol. Chem.
Abstract This study provides new perspectives of the unique aspects of platelet-derived growth factor beta-receptor (PDGFR-beta) signaling and biological responses through the establishment of a mutant mouse strain in which two loxP sequences were inserted into the introns of PDGFR-beta genome sequences. Isolation of skin fibroblasts from the mutant mice and Cre recombinase transfection in vitro induced PDGFR-beta gene deletion (PDGFR-betaDelta/Delta). The resultant depletion of the PDGFR-beta protein significantly attenuated platelet-derived growth factor (PDGF)-BB-induced cell migration, proliferation, and protection from H2O2-induced apoptosis of the cultured PDGFR-betaDelta/Delta dermal fibroblasts. PDGF-AA and fetal bovine serum were mitogenic and anti-apoptotic but were unable to induce the migration in PDGFR-beta Delta/Delta fibroblasts. Concerning the PDGF signaling, PDGF-BB-induced phosphorylation of Akt, ERK1/2, and JNK, but not p38, decreased in PDGFR-betaDelta/Delta fibroblasts, but PDGF-AA-induced signaling was not altered. Overexpression of the phospholipid phosphatases, SHIP2 and/or PTEN, inhibited PDGF-BB-induced phosphorylation of Akt and ERK1/2 in PDGFR-betaDelta/Delta fibroblasts but did not affect that of JNK and p38. These results indicate that disruption of distinct PDGFR-beta signaling pathways in PDGFR-betaDelta/Delta dermal fibroblasts impaired their proliferation and survival, but completely inhibits migratory response, and that PDGF-BB-induced phosphorylation of Akt and ERK1/2 possibly mediated by PDGFR-alpha is regulated, at least in part, by the lipid phosphatases SHIP2 and/or PTEN. Thus, the PDGFR-beta function on dermal fibroblasts appears to be critical in PDGF-BB action for skin wound healing and is clearly distinctive from that of PDGFR-alpha in the ligand-induced biological responses and the underlying properties of cellular signaling.
Volume 280(10)
Pages 9375-89
Published 2005-3-11
DOI 10.1074/jbc.M413081200
PII M413081200
PMID 15590688
MeSH Animals DNA Primers Fibroblasts / physiology* Gene Deletion* Genotype Humans Integrases / metabolism Mice Mice, Knockout Receptor, Platelet-Derived Growth Factor beta / deficiency Receptor, Platelet-Derived Growth Factor beta / genetics* Recombinant Proteins / metabolism Restriction Mapping Skin Transfection Wound Healing / physiology* Wounds and Injuries / genetics Wounds and Injuries / pathology*
IF 4.011
Times Cited 61
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material AxCANCre (RDB01748) AxCALNLNZ (RDB01750).