A Chemical and Genetic Approach to the Mode of Action of Fumagillin
| Autor: | Andrew Mara, Craig M. Crews, Igor Schneider, Diane C. Slusarski, Rong Ju, Scott A. Holley, Yi Zhang, John Hines, Jing Ruey Yeh, Pasquale Cirone, Hilary L. Griesbach |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Frizzled
Morpholino Cellular differentiation Clinical Biochemistry Dishevelled Proteins Angiogenesis Inhibitors 01 natural sciences Aminopeptidases Biochemistry Receptors G-Protein-Coupled Mice Drug Discovery Eye Abnormalities RNA Small Interfering Zebrafish 0303 health sciences Wnt signaling pathway LRP6 Metalloendopeptidases LRP5 General Medicine 3. Good health Cell biology Phenotype Fatty Acids Unsaturated Molecular Medicine Signal transduction Sesquiterpenes Signal Transduction Tail Molecular Sequence Data Embryonic Development Biology Wnt-5a Protein Cell Line 03 medical and health sciences Cyclohexanes Cell Line Tumor Animals Humans Molecular Biology 030304 developmental biology Adaptor Proteins Signal Transducing Pharmacology O-(Chloroacetylcarbamoyl)fumagillol 010405 organic chemistry JNK Mitogen-Activated Protein Kinases Endothelial Cells Oligonucleotides Antisense Zebrafish Proteins biology.organism_classification Phosphoproteins Frizzled Receptors 0104 chemical sciences Wnt Proteins Calcium-Calmodulin-Dependent Protein Kinases Calcium-Calmodulin-Dependent Protein Kinase Type 2 rhoA GTP-Binding Protein |
| Zdroj: | Chemistry & Biology. (9):1001-1009 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2006.07.010 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|