2010
DOI: 10.1038/nchembio.362
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Small-molecule inhibition of APT1 affects Ras localization and signaling

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 e… Show more

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Cited by 363 publications
(431 citation statements)
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“…However, because Palm B inhibits both Apt1 and Apt2 (30,31), generalized inhibition of these cytosolic thioesterases may not clearly answer our question. Therefore, we first performed experiments in which cultured astrocytes were transfected with either scrambled shRNA (control) or APT1 shRNA and determined the levels of Apt1 expression.…”
Section: Resultsmentioning
confidence: 69%
See 1 more Smart Citation
“…However, because Palm B inhibits both Apt1 and Apt2 (30,31), generalized inhibition of these cytosolic thioesterases may not clearly answer our question. Therefore, we first performed experiments in which cultured astrocytes were transfected with either scrambled shRNA (control) or APT1 shRNA and determined the levels of Apt1 expression.…”
Section: Resultsmentioning
confidence: 69%
“…Although the specific PATs that catalyze palmitoylation of APT1 and APT2 have yet to be identified, we speculated that APT1 and APT2 may catalyze their own depalmitoylation or they catalyze depalmitoylation of each other to promote their dynamic palmitoylation, promoting steady-state membrane localization and function. Accordingly, we performed Western blot analysis of cytosolic and membrane fractions of cultured astrocytes that were treated with either DMSO (control) or with varying doses of Palm B, first reported to be a catalytic inhibitor of APT1 (30) but subsequently found to inhibit both APT1 and APT2 (31). The results suggested that although Apt1 (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…To explore whether MC1R palmitoylation is dynamic, we removed α-MSH from the culture medium and found that palmitoylation disappeared within 12 h, while Palm-B, a deacylating enzyme inhibitor 28,29 , blocked both WT and R151C MC1R depalmitoylation (Extended Data Fig. 7a), suggesting that Palm-B enhances MC1R palmitoylation.…”
mentioning
confidence: 99%
“…In mammalian cells, targeting APT1 with b-lactone inhibitors was shown to have severe consequences in oncogenic Ras-transformed fibroblasts (Dekker et al, 2010), however it was later shown that these inhibitors have multiple targets (Rusch et al, 2011), including both APT1 and APT2, and it is unknown whether targeting APT1 alone (either by more specific chemical means or through gene disruption) would produce the same effect. The same b-lactone inhibitors, when used on T. gondii, are highly toxic at levels required to block TgPPT1 and hit multiple targets (Kemp et al, 2013).…”
Section: Discussionmentioning
confidence: 99%