Small-molecule inhibition of APT1 affects Ras localization and signaling

Tools

Item Type:	Article
Title:	Small-molecule inhibition of APT1 affects Ras localization and signaling
Creators Name:	Dekker, F.J., Rocks, O., Vartak, N., Menninger, S., Hedberg, C., Balamurugan, R., Wetzel, S., Renner, S., Gerauer, M., Schoelermann, B., Rusch, M., Kramer, J.W., Rauh, D., Coates, G.W., Brunsveld, L., Bastiaens, P.I. and Waldmann, H.
Abstract:	Cycles of depalmitoylation and repalmitoylation critically control the steady-state localization and function of various peripheral membrane proteins, such as Ras proto-oncogene products. Interference with acylation using small molecules is a strategy to modulate cellular localization--and thereby unregulated signaling--caused by palmitoylated Ras proteins. We present the knowledge-based development and characterization of a potent inhibitor of acyl protein thioesterase 1 (APT1), a bona fide depalmitoylating enzyme that is, so far, poorly characterized in cells. The inhibitor, palmostatin B, perturbs the cellular acylation cycle at the level of depalmitoylation and thereby causes a loss of the precise steady-state localization of palmitoylated Ras. As a consequence, palmostatin B induces partial phenotypic reversion in oncogenic HRasG12V-transformed fibroblasts. We identify APT1 as one of the thioesterases in the acylation cycle and show that this protein is a cellular target of the inhibitor.
Keywords:	Cell Line, Down-Regulation, Enzyme Inhibitors, Kidney, Ligands, Lipase, Lipoylation, Molecular Models, Protein Conformation, Signal Transduction, Stomach, Thiolester Hydrolases, ras Proteins, Animals, Dogs
Source:	Nature Chemical Biology
ISSN:	1552-4450
Publisher:	Nature Publishing Group
Volume:	6
Number:	6
Page Range:	449-456
Date:	June 2010
Official Publication:	https://doi.org/10.1038/nchembio.362
PubMed:	View item in PubMed

Repository Staff Only: item control page