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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Aminopeptidases / antagonists & inhibitors
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Aminopeptidases / genetics
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Aminopeptidases / metabolism*
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Cell Line, Tumor
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Cyclohexanes / pharmacology*
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Dishevelled Proteins
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Embryonic Development / drug effects
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Embryonic Development / genetics
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Endothelial Cells / metabolism
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Eye Abnormalities / chemically induced
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Eye Abnormalities / genetics
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Fatty Acids, Unsaturated / pharmacology*
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Frizzled Receptors
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism*
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Mice
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Molecular Sequence Data
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O-(Chloroacetylcarbamoyl)fumagillol
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Oligonucleotides, Antisense / pharmacology
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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RNA, Small Interfering / genetics
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Receptors, G-Protein-Coupled
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Sesquiterpenes / pharmacology*
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Signal Transduction / drug effects
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Tail / abnormalities
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Tail / chemistry
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt-5a Protein
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Zebrafish / embryology
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Zebrafish / genetics*
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Zebrafish / metabolism
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Zebrafish Proteins / antagonists & inhibitors
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism*
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rhoA GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Angiogenesis Inhibitors
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Cyclohexanes
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Dishevelled Proteins
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Fatty Acids, Unsaturated
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Frizzled Receptors
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Fzd2 protein, mouse
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Oligonucleotides, Antisense
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Phosphoproteins
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Sesquiterpenes
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Wnt Proteins
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Wnt-5a Protein
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Wnt5a protein, zebrafish
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Zebrafish Proteins
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fumagillin
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Aminopeptidases
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methionine aminopeptidase-2, zebrafish
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methionine aminopeptidase 2
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Metalloendopeptidases
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rhoA GTP-Binding Protein
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O-(Chloroacetylcarbamoyl)fumagillol