Small-molecule inhibition of APT1 affects Ras localization and signaling

被引：301

作者：

Dekker, Frank J. ^{[1
,2
]}

Rocks, Oliver ^{[3
]}

Vartak, Nachiket ^{[3
]}

Menninger, Sascha ^{[1
,2
]}

Hedberg, Christian ^{[1
,2
]}

Balamurugan, Rengarajan ^{[1
,2
]}

Wetzel, Stefan ^{[1
,2
]}

Renner, Steffen ^{[1
,2
]}

Gerauer, Marc ^{[1
,2
]}

Schoelermann, Beate ^{[2
]}

Rusch, Marion ^{[1
,2
]}

Kramer, John W. ^{[4
]}

Rauh, Daniel ^{[5
]}

Coates, Geoffrey W. ^{[4
]}

Brunsveld, Luc ^{[1
,2
]}

Bastiaens, Philippe I. H. ^{[1
,3
]}

Waldmann, Herbert ^{[1
,2
]}

机构：

[1] Univ Dortmund, Fachbereich Chem, D-4600 Dortmund, Germany

[2] Max Planck Inst Mol Physiol, Dept Biol Chem, D-44139 Dortmund, Germany

[3] Max Planck Inst Mol Physiol, Dept Syst Cell Biol, D-44139 Dortmund, Germany

[4] Baker Lab, Dept Chem & Biol Chem, Ithaca, NY USA

[5] Max Planck Gesell, Chem Genom Ctr, Dortmund, Germany

来源：

NATURE CHEMICAL BIOLOGY | 2010年 / 6卷 / 06期

关键词：

ACYL-PROTEIN THIOESTERASE; CRYSTAL-STRUCTURE; 2-BROMOPALMITATE; PALMITOYLATION; LIPASE; INVASION; COMPLEX;

D O I：

10.1038/nchembio.362

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：449 / 456

页数：8

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