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Small-molecule inhibition of APT1 affects Ras localization and signaling

Item Type:Article
Title:Small-molecule inhibition of APT1 affects Ras localization and signaling
Creators Name:Dekker, F.J. and Rocks, O. and Vartak, N. and Menninger, S. and Hedberg, C. and Balamurugan, R. and Wetzel, S. and Renner, S. and Gerauer, M. and Schoelermann, B. and Rusch, M. and Kramer, J.W. and Rauh, D. and Coates, G.W. and Brunsveld, L. and 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
Publisher:Nature Publishing Group
Page Range:449-456
Date:June 2010
Official Publication:https://doi.org/10.1038/nchembio.362
PubMed:View item in PubMed

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