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Interference with platelet‐derived growth factor‐induced activation of receptor tyrosine kinase and downstream signaling pathways by compound C
Author(s) -
Yeo Eui-Ju,
Kim Go-Eun,
Kwon Hyun Jin,
Jeong Meong-Sook,
Lee Yoon-Taek
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.761.24
Subject(s) - platelet derived growth factor receptor , protein kinase b , ampk , microbiology and biotechnology , phosphorylation , chemistry , receptor tyrosine kinase , pi3k/akt/mtor pathway , tyrosine phosphorylation , signal transduction , tyrosine kinase , cancer research , biology , protein kinase a , receptor , growth factor , biochemistry
Although AMP‐activated protein kinase (AMPK) activation has been implicated in anti‐proliferative actions in various cell systems, we have observed that compound C, an inhibitor of AMPK, reduced the cell viability of human diploid fibroblasts (HDFs). Flow cytometry revealed blocking of cell cycle progression by compound C. Preincubation of HDFs with compound C abrogated PDGF‐induced Akt phosphorylation. Compound C did not affect Akt activity in vitro . Compound C completely inhibited PDGF‐induced phosphorylation of PDGF receptor‐β, which thereby could block downstream PDGF‐induced PI3K, Akt, and ERK1/2. Compound C did not affect EGF‐ and IGF‐induced receptor tyrosine phosphorylation and downstream signaling. In vitro receptor tyrosine kinase activity profiling revealed that IC50 for PDGFR was 5.07 μM for PDGFRβ, whereas IC50 for EGFR and IGF1R was over 100 μM. The inhibitory effect of compound C on PDGF receptor‐β and Akt phosphorylation was also observed in AMPKα1/α2‐knockout MEF cells, indicating that the inhibitory effect of compound C is independent of regulating the AMPK activity. These results suggest that the inhibitory effect of compound C on the PDGF‐BB‐induced proliferation of HDFs is mediated by blocking tyrosine kinase activity of PDGFRβ and downstream signaling pathways, which is independent of regulating AMPK activity [Research support: KRF # 2010‐000‐ 4564 and # 2011‐000‐5951].