ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth
| Autor: | Amanda Long, Anagha Inguva, Marina Predovic, Jarrett R. Remsberg, Thomas W. Hanigan, Stewart K. Richardson, Noemi A. Zambetti, Micah J. Niphakis, Nhi Ngo, Amy R. Howell, Cassandra L. Henry, Ari J. Firestone, Benjamin F. Cravatt, Kenneth M. Lum, Ben Huang, Kevin Shannon, Radu M. Suciu, Melissa M. Dix |
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| Rok vydání: | 2021 |
| Předmět: |
Myeloid
Biochemistry & Molecular Biology Hydrolases Childhood Leukemia Pediatric Cancer Cells Lipoylation Acute Oncogenicity Medicinal and Biomolecular Chemistry 03 medical and health sciences Rare Diseases Palmitoylation Microsomes Humans Molecular Biology Cell Proliferation Cancer 030304 developmental biology Promyelocytic Pediatric chemistry.chemical_classification 0303 health sciences Cultured Leukemia Molecular Structure biology Kinase Cell Membrane 030302 biochemistry & molecular biology Myeloid leukemia Hematology Cell Biology Cell biology Enzyme Liver chemistry Mitogen-activated protein kinase Proteome Lipase inhibitors ras Proteins biology.protein Biochemistry and Cell Biology |
| Zdroj: | Nature chemical biology, vol 17, iss 8 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/s41589-021-00785-8 |
| Popis: | Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers. |
| Databáze: | OpenAIRE |
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