Positional proteomics and MetAP-2 substrates

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 (2011) Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation Chemistry & Biology (2011), doi:10.1016/j.chembiol.2011.07.020 of the MetAP-2 Substrate Rab37 [PUBMED][PDF]

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.

Screen Shot 2011-12-07 at 08.24.50