Small-molecule inhibition of APT1 affects Ras localization and signaling
Small-molecule inhibition of APT1 affects Ras localization and signaling
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DOI：
10.1038/nchembio.362
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发表时间：
2010-06-01
影响因子：
14.8
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
--
作者：
Dekker, Frank J.;Rocks, Oliver;Waldmann, Herbert
去棕榈酰化和再棕榈酰化的循环严格控制各种外周膜蛋白的稳态定位和功能，如Ras原癌基因产物。使用小分子干扰酰化是调节棕榈酰化Ras蛋白引起的细胞定位从而调节不受调节的信号传导的策略。我们提出了一种有效的酰基蛋白硫酯酶1（APT1），一个真正的脱棕榈酰化酶，是，到目前为止，在细胞中的特点差的抑制剂的知识为基础的发展和表征。抑制剂帕莫司他丁B在去棕榈酰化水平扰乱细胞酰化循环，从而导致棕榈酰化Ras的精确稳态定位丧失。因此，帕莫司他丁B诱导致癌HRasG 12 V转化成纤维细胞的部分表型逆转。我们确定APT1作为酰化循环中的硫酯酶之一，并表明这种蛋白质是抑制剂的细胞靶点。
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.