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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Vydáno v:	Nature chemical biology Ročník 6; číslo 6; s. 449 - 456
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.06.2010 Nature Publishing Group
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/nchembio.362