Small-molecule inhibition of APT1 affects Ras localization and signaling

Reversible palmitoylation controls the localization and signaling of Ras. Development of a potent and specific small molecule inhibitor of the thioesterase APT1 reveals that this enzyme depalmitoylates Ras in cells. Inhibition of APT1 led to redistribution and altered activity of HRas, NRas and an o...

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Published in:Nature chemical biology Vol. 6; no. 6; pp. 449 - 456
Main Authors: Dekker, Frank J, Rocks, Oliver, Vartak, Nachiket, Menninger, Sascha, Hedberg, Christian, Balamurugan, Rengarajan, Wetzel, Stefan, Renner, Steffen, Gerauer, Marc, Schölermann, Beate, Rusch, Marion, Kramer, John W, Rauh, Daniel, Coates, Geoffrey W, Brunsveld, Luc, Bastiaens, Philippe I H, Waldmann, Herbert
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.06.2010
Nature Publishing Group
Subjects:
631/80/2023
631/80/86
631/92/613
Animals
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell division
Cell Line
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Dogs
Down-Regulation
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Genes
Humans
Inhibitor drugs
Kidney - drug effects
Kidney - physiology
Ligands
Lipase - chemistry
Lipase - metabolism
Lipoylation - drug effects
Models, Molecular
Molecules
Propiolactone - analogs & derivatives
Propiolactone - chemical synthesis
Propiolactone - chemistry
Propiolactone - pharmacology
Protein Conformation
Proteins
ras Proteins - drug effects
ras Proteins - metabolism
ras Proteins - physiology
Signal Transduction
Stomach - enzymology
Thiolester Hydrolases - antagonists & inhibitors
Thiolester Hydrolases - chemistry
Thiolester Hydrolases - genetics
ISSN:1552-4450, 1552-4469, 1552-4469
Online Access:Get full text
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Summary:Reversible palmitoylation controls the localization and signaling of Ras. Development of a potent and specific small molecule inhibitor of the thioesterase APT1 reveals that this enzyme depalmitoylates Ras in cells. Inhibition of APT1 led to redistribution and altered activity of HRas, NRas and an oncogenic mutant Ras. 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.
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ISSN:1552-4450
1552-4469
1552-4469
DOI:10.1038/nchembio.362