Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37

Thomas B Sundberg; Nicole Darricarrere; Pasquale Cirone; Xia Li; Lucy McDonald; Xue Mei; Christopher J Westlake; Diane C Slusarski; Robert J Beynon; Craig M Crews

doi:10.1016/j.chembiol.2011.07.020

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Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37

Journal article

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Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37

Thomas B Sundberg, Nicole Darricarrere, Pasquale Cirone, Xia Li, Lucy McDonald, Xue Mei, Christopher J Westlake, Diane C Slusarski, Robert J Beynon and Craig M Crews

Chemistry & biology, Vol.18(10), pp.1300-1311

10/28/2011

DOI: 10.1016/j.chembiol.2011.07.020

PMCID: PMC3205358

PMID: 22035799

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Abstract

Identification of methionine aminopeptidase-2 (MetAP-2) as the molecular target of the antiangiogenic compound TNP-470 has sparked interest in N-terminal Met excision's (NME) role in endothelial cell biology. In this regard, we recently demonstrated that MetAP-2 inhibition suppresses Wnt planar cell polarity (PCP) signaling and that endothelial cells depend on this pathway for normal function. Despite this advance, the substrate(s) whose activity is altered upon MetAP-2 inhibition, resulting in loss of Wnt PCP signaling, is not known. Here we identify the small G protein Rab37 as a MetAP-2-specific substrate that accumulates in the presence of TNP-470. A functional role for aberrant Rab37 accumulation in TNP-470's mode of action is demonstrated using a Rab37 point mutant that is resistant to NME, because expression of this mutant phenocopies the effects of MetAP-2 inhibition on Wnt PCP signaling-dependent processes. [Display omitted] ► N-terminal positional proteomics identifies Rab37 as a specific MetAP-2 substrate ► Rab37 appears to play a role in plasma membrane-to-Golgi trafficking ► Aberrant Rab37 accumulation disrupts normal endothelial cell function ► Rab37 expression perturbs Wnt PCP-dependent processes during zebrafish development

Details

Title: Subtitle: Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37
Creators: Thomas B Sundberg - Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA
Nicole Darricarrere - Department of Cell Biology, Yale University, New Haven, CT 06511, USA
Pasquale Cirone - Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA
Xia Li - Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA
Lucy McDonald - Protein Function Group, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
Xue Mei - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Christopher J Westlake - Genentech, South San Francisco, CA 94080, USA
Diane C Slusarski - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Robert J Beynon - Protein Function Group, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
Craig M Crews - Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA
Resource Type: Journal article
Publication Details: Chemistry & biology, Vol.18(10), pp.1300-1311
DOI: 10.1016/j.chembiol.2011.07.020
PMID: 22035799
PMCID: PMC3205358
NLM abbreviation: Chem Biol
ISSN: 1074-5521
eISSN: 1879-1301
Publisher: Elsevier Ltd
Language: English
Date published: 10/28/2011
Academic Unit: Iowa Neuroscience Institute; Biology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984070620102771

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