Work

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

Year: 2007

Type: peer-review

Abstract: Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the anti-angiogenic 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 pheno-copies 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.

Source: Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

DOI: 10.3410/f.1069813.522750

Author: Benjamin Cravatt

Institution: Scripps Research Institute

Language: English

Topic: Wnt/β-catenin signaling in development and cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institutes of Health