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| Item Type: | Article |
|---|---|
| Title: | Small-molecule inhibition of APT1 affects Ras localization and signaling |
| Creators Name: | Dekker, F.J., Rocks, O., Vartak, N., Menninger, S., Hedberg, C., Balamurugan, R., Wetzel, S., Renner, S., Gerauer, M., Schoelermann, B., Rusch, M., Kramer, J.W., Rauh, D., Coates, G.W., Brunsveld, L., Bastiaens, P.I. and Waldmann, H. |
| 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. |
| Keywords: | Cell Line, Down-Regulation, Enzyme Inhibitors, Kidney, Ligands, Lipase, Lipoylation, Molecular Models, Protein Conformation, Signal Transduction, Stomach, Thiolester Hydrolases, ras Proteins, Animals, Dogs |
| Source: | Nature Chemical Biology |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Volume: | 6 |
| Number: | 6 |
| Page Range: | 449-456 |
| Date: | June 2010 |
| Official Publication: | https://doi.org/10.1038/nchembio.362 |
| PubMed: | View item in PubMed |
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