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

Yi Zhang; Jing Ruey Yeh; Andrew Mara; Rong Ju; John F Hines; Pasquale Cirone; Hilary L Griesbach; Igor Schneider; Diane C Slusarski; Scott A Holley; Craig M Crews

doi:10.1016/j.chembiol.2006.07.010

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

Journal article

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

Yi Zhang, Jing Ruey Yeh, Andrew Mara, Rong Ju, John F Hines, Pasquale Cirone, Hilary L Griesbach, Igor Schneider, Diane C Slusarski, Scott A Holley, …

Chemistry & biology, Vol.13(9), pp.1001-1009

09/2006

DOI: 10.1016/j.chembiol.2006.07.010

PMCID: PMC2583369

PMID: 16984890

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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.

Phenotype

Metalloendopeptidases - genetics

RNA, Small Interfering - genetics

Cyclohexanes - pharmacology

Humans

Molecular Sequence Data

JNK Mitogen-Activated Protein Kinases - metabolism

Metalloendopeptidases - metabolism

rhoA GTP-Binding Protein - metabolism

Wnt-5a Protein

Phosphoproteins - metabolism

Wnt Proteins - metabolism

Zebrafish - embryology

Wnt Proteins - genetics

Tail - chemistry

Dishevelled Proteins

Eye Abnormalities - chemically induced

Aminopeptidases - metabolism

Calcium-Calmodulin-Dependent Protein Kinase Type 2

Frizzled Receptors

Metalloendopeptidases - antagonists & inhibitors

Cell Line

Aminopeptidases - genetics

Oligonucleotides, Antisense - pharmacology

Endothelial Cells - metabolism

Zebrafish Proteins - metabolism

Zebrafish Proteins - antagonists & inhibitors

Embryonic Development - genetics

Receptors, G-Protein-Coupled

Angiogenesis Inhibitors - pharmacology

Fatty Acids, Unsaturated - pharmacology

Aminopeptidases - antagonists & inhibitors

Phosphoproteins - genetics

Eye Abnormalities - genetics

Zebrafish - genetics

Animals

Tail - abnormalities

Signal Transduction - drug effects

Zebrafish - metabolism

Adaptor Proteins, Signal Transducing - genetics

Cell Line, Tumor

Mice

Sesquiterpenes - pharmacology

Zebrafish Proteins - genetics

Adaptor Proteins, Signal Transducing - metabolism

Embryonic Development - drug effects

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Details

Title: Subtitle: A chemical and genetic approach to the mode of action of fumagillin
Creators: Yi Zhang - Yale University
Jing Ruey Yeh
Andrew Mara
Rong Ju
John F Hines - Yale University
Pasquale Cirone
Hilary L Griesbach
Igor Schneider
Diane C Slusarski
Scott A Holley
Craig M Crews
Resource Type: Journal article
Publication Details: Chemistry & biology, Vol.13(9), pp.1001-1009
DOI: 10.1016/j.chembiol.2006.07.010
PMID: 16984890
PMCID: PMC2583369
NLM abbreviation: Chem Biol
ISSN: 1074-5521
eISSN: 1879-1301
Publisher: United States
Grant note: R01 CA083049 / NCI NIH HHS CA112369 / NCI NIH HHS R01 CA083049-08 / NCI NIH HHS R01 CA112369 / NCI NIH HHS CA083049 / NCI NIH HHS
Language: English
Date published: 09/2006
Academic Unit: Biology
Record Identifier: 9983992062502771

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