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J. Biol. Chem., Vol. 280, Issue 10, 9375-9389, March 11, 2005

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Deletion of the PDGFR- Gene Affects Key Fibroblast Functions Important for Wound Healing^*

Zhiyang Gao, Toshiyasu Sasaoka, Toshihiko Fujimori¶, Takeshi Oya, Yoko Ishii, Hemragul Sabit, Makoto Kawaguchi||, Yoko Kurotaki¶, Maiko Naito, Tsutomu Wada**, Shin Ishizawa, Masashi Kobayashi**, Yo-Ichi Nabeshima¶, and Masakiyo Sasahara

From the Department of Pathology, the Department of Clinical Pharmacology and the ^**First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, the ^¶Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, the ^||Department of Pathology, Niigata Rosai Hospital, Labor Health and Welfare Organization, 1-7-12 Tooun-cho, Jhoetsu, Niigata 942-8502, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan

This study provides new perspectives of the unique aspects of platelet-derived growth factor -receptor (PDGFR-) signaling and biological responses through the establishment of a mutant mouse strain in which two loxP sequences were inserted into the introns of PDGFR- genome sequences. Isolation of skin fibroblasts from the mutant mice and Cre recombinase transfection in vitro induced PDGFR- gene deletion (PDGFR- ^/). The resultant depletion of the PDGFR- protein significantly attenuated platelet-derived growth factor (PDGF)-BB-induced cell migration, proliferation, and protection from H₂O₂-induced apoptosis of the cultured PDGFR- ^/ dermal fibroblasts. PDGF-AA and fetal bovine serum were mitogenic and anti-apoptotic but were unable to induce the migration in PDGFR- ^/ fibroblasts. Concerning the PDGF signaling, PDGF-BB-induced phosphorylation of Akt, ERK1/2, and JNK, but not p38, decreased in PDGFR- ^/ 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- ^/ fibroblasts but did not affect that of JNK and p38. These results indicate that disruption of distinct PDGFR- signaling pathways in PDGFR- ^/ 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- is regulated, at least in part, by the lipid phosphatases SHIP2 and/or PTEN. Thus, the PDGFR- function on dermal fibroblasts appears to be critical in PDGF-BB action for skin wound healing and is clearly distinctive from that of PDGFR- in the ligand-induced biological responses and the underlying properties of cellular signaling.

Received for publication, November 19, 2004

^* This study was supported in part by Grants-in-aid for Scientific Research 16390114 and 12470053 from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pathology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: 81-76-434-7238; Fax: 81-76-434-5016; E-mail: sasahara{at}ms.toyama-mpu.ac.jp.

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