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Binding of Fumagillin to the Cytoplasmic Domain of FGFR‐1 Leads to Inhibition of FGF‐1‐stimulated Angiogenesis via the PI3K/AKT Signaling Pathway
Author(s) -
Chen Gregory J
Publication year - 2006
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.20.4.a31-a
Subject(s) - fumagillin , angiogenesis , fibroblast growth factor , biology , protein kinase b , pi3k/akt/mtor pathway , microbiology and biotechnology , signal transduction , biochemistry , cancer research , receptor
Objectives Fibroblast growth factor‐1 (FGF‐1), a prototypic member of the FGF family, is a potent angiogenic factor. Fumagillin, an antiangiogenic fungal metabolite, has the ability to inhibit FGF‐stimulated angiogenesis in the chicken chorioallantoic membrane (CAM). In our current study we investigate the signaling mechanism by which fumagillin inhibits FGF‐1‐stimulated angiogenesis in CAM. Day eight chicken CAMs were transfected with a signal peptide‐containing version of the FGF‐1 gene construct (sp‐FGF‐1). Transfected CAMs were then analyzed in the presence and absence of fumagillin treatment with respect to the mRNA expression levels and protein activity of the FGF‐1 receptor protein (FGFR‐1), PI3K (phosphatidylinositol 3‐kinase), and its immediate downstream target, AKT‐1 (protein kinase B). In post treatment of sp‐FGF‐1‐ transfected CAMs by fumagillin, we found down‐regulation for both PI3K and AKT‐1 proteins in mRNA expression and protein activity. In contrast, we did not detect any major alterations in FGFR‐1 mRNA expression level. To further investigate the site of inhibition by fumagillin along the PI3K signaling pathway, biotin‐labeled fumagillin was individually incubated with recombinant FGFR‐1, PI3K, and AKT‐1 proteins. Only the FGF‐1 receptor protein containing the cytoplasmic domain (amino acids 456‐765) demonstrated binding to fumagillin. Based on these findings, we conclude that the binding of fumagillin to the cytoplasmic domain of the FGF‐1 receptor containing the tyrosine residues inhibited the FGF‐1‐stimulated angiogenesis in vivo . Furthermore, our results suggest that fumagillin inhibits FGF‐1‐stimulated angiogenesis by disrupting the downstream PI3K/AKT signaling pathway.