A chemical and genetic approach to the mode of action of fumagillin.
Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the antiangiogenic natural product fumagillin and its drug candidate analog, TNP-470. We report here that TNP-470-mediated MetAP-2 inhibition blocks noncanonical Wnt signaling, which plays a critical role in development, cell differentiation, and tumorigenesis. Consistent with this finding, antisense MetAP-2 morpholino oligonucleotide injection in zebrafish embryos phenocopies gastrulation defects seen in noncanonical Wnt5 loss-of-function zebrafish mutants. MetAP-2 inhibition or depletion blocks signaling downstream of the Wnt receptor Frizzled, but upstream of Calmodulin-dependent Kinase II, RhoA, and c-Jun N-terminal Kinase. Moreover, we demonstrate that TNP-470 does not block the canonical Wnt/beta-catenin pathway. Thus, TNP-470 selectively regulates noncanonical over canonical Wnt signaling and provides a unique means to explore and dissect the biological systems mediated by these pathways.
Pubmed ID: 16984890 RIS Download
Adaptor Proteins, Signal Transducing | Aminopeptidases | Angiogenesis Inhibitors | Animals | Calcium-Calmodulin-Dependent Protein Kinase Type 2 | Calcium-Calmodulin-Dependent Protein Kinases | Cell Line | Cell Line, Tumor | Cyclohexanes | Embryonic Development | Endothelial Cells | Eye Abnormalities | Fatty Acids, Unsaturated | Frizzled Receptors | Humans | JNK Mitogen-Activated Protein Kinases | Metalloendopeptidases | Mice | Molecular Sequence Data | Oligonucleotides, Antisense | Phenotype | Phosphoproteins | RNA, Small Interfering | Receptors, G-Protein-Coupled | Sesquiterpenes | Signal Transduction | Tail | Wnt Proteins | Zebrafish | Zebrafish Proteins | rhoA GTP-Binding Protein