A chemical and genetic approach to the mode of action of fumagillin |
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| Authors: | Zhang Yi Yeh Jing Ruey Mara Andrew Ju Rong Hines John F Cirone Pasquale Griesbach Hilary L Schneider Igor Slusarski Diane C Holley Scott A Crews Craig M |
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| Institution: | Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA. |
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| 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 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. |
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