ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
03
03
2020
accepted:
10
03
2021
revised:
02
03
2021
pubmed:
1
5
2021
medline:
8
9
2021
entrez:
30
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33927411
doi: 10.1038/s41589-021-00785-8
pii: 10.1038/s41589-021-00785-8
pmc: PMC8900659
mid: NIHMS1781729
doi:
Substances chimiques
ABHD17B protein, human
EC 3.-
Hydrolases
EC 3.-
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
856-864Subventions
Organisme : NCI NIH HHS
ID : R01 CA238249
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073831
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193994
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231991
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA072614
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA072614
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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