PUBLICATION
A chemical and genetic approach to the mode of action of fumagillin
- Authors
- Zhang, Y., Yeh, J.R., Mara, A., Ju, R., Hines, J.F., Cirone, P., Griesbach, H.L., Schneider, I., Slusarski, D.C., Holley, S.A., and Crews, C.M.
- ID
- ZDB-PUB-060921-27
- Date
- 2006
- Source
- Chemistry & Biology 13(9): 1001-1009 (Journal)
- Registered Authors
- Slusarski, Diane C.
- Keywords
- none
- MeSH Terms
-
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- Zebrafish/embryology
- Zebrafish/genetics*
- Zebrafish/metabolism
- Eye Abnormalities/chemically induced
- Eye Abnormalities/genetics
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- JNK Mitogen-Activated Protein Kinases/metabolism
- Cyclohexanes/pharmacology*
- Fatty Acids, Unsaturated/pharmacology*
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Molecular Sequence Data
- Cell Line, Tumor
- Oligonucleotides, Antisense/pharmacology
- Frizzled Receptors
- Embryonic Development/drug effects
- Embryonic Development/genetics
- Mice
- Tail/abnormalities
- Tail/chemistry
- Signal Transduction/drug effects
- Phenotype
- rhoA GTP-Binding Protein/metabolism
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Endothelial Cells/metabolism
- Aminopeptidases/antagonists & inhibitors
- Aminopeptidases/genetics
- Aminopeptidases/metabolism*
- Sesquiterpenes/pharmacology*
- Cell Line
- Wnt Proteins/genetics
- Wnt Proteins/metabolism*
- Angiogenesis Inhibitors/pharmacology*
- Metalloendopeptidases/antagonists & inhibitors
- Metalloendopeptidases/genetics
- Metalloendopeptidases/metabolism*
- RNA, Small Interfering/genetics
- Calcium-Calmodulin-Dependent Protein Kinases/metabolism
- Animals
- Receptors, G-Protein-Coupled
- Humans
- PubMed
- 16984890 Full text @ Chem. Biol.
Citation
Zhang, Y., Yeh, J.R., Mara, A., Ju, R., Hines, J.F., Cirone, P., Griesbach, H.L., Schneider, I., Slusarski, D.C., Holley, S.A., and Crews, C.M. (2006) A chemical and genetic approach to the mode of action of fumagillin. Chemistry & Biology. 13(9):1001-1009.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping