A chemical and genetic approach to the mode of action of fumagillin.
Journal:
Chem. Biol. 2006 SepAuthors:
Zhang Y, Yeh JR, Mara A, Ju R, Hines JF, Cirone P, Griesbach HL, Schneider I, Slusarski DC, Holley SA, Crews CM
Abstract
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 s
...[more]een 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.[less]
Mesh Headings:
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