Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37.
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.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Thomas B
TB
Sundberg
Nicole
N
Darricarrere
Pasquale
P
Cirone
Xia
X
Li
Lucy
L
McDonald
Xue
X
Mei
Christopher J
CJ
Westlake
Diane C
DC
Slusarski
Robert J
RJ
Beynon
Craig M
CM
Crews
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D016764:Cell Polarity; D049109:Cell Proliferation; D003510:Cyclohexanes / Q000494:pharmacology; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006131:Growth Inhibitors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D000072261:Dishevelled Proteins; D005231:Fatty Acids, Unsaturated; D006131:Growth Inhibitors; D010750:Phosphoproteins; D012717:Sesquiterpenes; D029961:Zebrafish Proteins; C026211:fumagillin; D000626:Aminopeptidases; C571082:methionine aminopeptidase-2, zebrafish; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; C571080:Rab37 protein, human; C571081:Rab37 protein, zebrafish; D020691:rab GTP-Binding Proteins; D000077609:O-(Chloroacetylcarbamoyl)fumagillol