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- Title
Small-molecule inhibition of APT1 affects Ras localization and signaling.
- 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
- 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.
- Publication
Nature chemical biology, 2010, Vol 6, Issue 6, p449
- ISSN
1552-4469
- Publication type
Journal Article
- DOI
10.1038/nchembio.362