Small-molecule inhibition of APT1 affects Ras localization and signaling

F.J. Dekker, O. Rocks, N. Vartak, S. Menninger, C. Hedberg, R. Balamurugan, S. Wetzel, S. Renner, M. Gerauer, B. Schölermann, M. Rusch, J.W. Kramer, D. Rauh, G.W. Coates, L. Brunsveld, P.I.H. Bastiaens, H. Waldmann

Research output: Contribution to journalArticleAcademicpeer-review

237 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)449-456
Number of pages8
JournalNature Chemical Biology
Volume6
Issue number6
DOIs
Publication statusPublished - 2010

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