Author/Authors :
Yi Zhang، نويسنده , , Jing Ruey Yeh، نويسنده , , Andrew Mara، نويسنده , , Rong Ju، نويسنده , , John F. Hines، نويسنده , , Pasquale Cirone، نويسنده , , Hilary L. Griesbach، نويسنده , , Igor Schneider، نويسنده , , Diane C. Slusarski، نويسنده , , Scott A. Holley، نويسنده , , Craig M. Crews، نويسنده ,
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/β-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.
