| Literature DB >> 16984890 |
Yi Zhang1, Jing Ruey Yeh, Andrew Mara, Rong Ju, John F Hines, Pasquale Cirone, Hilary L Griesbach, Igor Schneider, Diane C Slusarski, Scott A Holley, Craig M Crews.
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.Entities:
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Year: 2006 PMID： 16984890 PMCID： PMC2583369 DOI： 10.1016/j.chembiol.2006.07.010
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521