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A chemical and genetic approach to the mode of action of fumagillin.

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.

Pubmed ID: 16984890

Authors

  • Zhang Y
  • Yeh JR
  • Mara A
  • Ju R
  • Hines JF
  • Cirone P
  • Griesbach HL
  • Schneider I
  • Slusarski DC
  • Holley SA
  • Crews CM

Journal

Chemistry & biology

Publication Data

September 20, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA083049
  • Agency: NCI NIH HHS, Id: CA112369
  • Agency: NCI NIH HHS, Id: R01 CA083049
  • Agency: NCI NIH HHS, Id: R01 CA083049-08
  • Agency: NCI NIH HHS, Id: R01 CA112369

Mesh Terms

  • 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