Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37

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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. © 2011 Elsevier Ltd All rights reserved.

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Sundberg, T. B., Darricarrere, N., Cirone, P., Li, X., McDonald, L., Mei, X., … Crews, C. M. (2011). Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37. Chemistry and Biology, 18(10), 1300–1311. https://doi.org/10.1016/j.chembiol.2011.07.020

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