Title : ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth - Remsberg_2021_Nat.Chem.Biol__ |
Author(s) : Remsberg JR , Suciu RM , Zambetti NA , Hanigan TW , Firestone AJ , Inguva A , Long A , Ngo N , Lum KM , Henry CL , Richardson SK , Predovic M , Huang B , Dix MM , Howell AR , Niphakis MJ , Shannon K , Cravatt BF |
Ref : Nat Chemical Biology , : , 2021 |
Abstract :
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. |
PubMedSearch : Remsberg_2021_Nat.Chem.Biol__ |
PubMedID: 33927411 |
Gene_locus related to this paper: human-ABHD17A , human-ABHD17B , human-ABHD17C |
Inhibitor | ABD957 CID155803786 CID155803792 CID155803782 CID155803778 |
Gene_locus | human-ABHD17A human-ABHD17B human-ABHD17C |
Family | ABHD17-depalmitoylase |
Remsberg JR, Suciu RM, Zambetti NA, Hanigan TW, Firestone AJ, Inguva A, Long A, Ngo N, Lum KM, Henry CL, Richardson SK, Predovic M, Huang B, Dix MM, Howell AR, Niphakis MJ, Shannon K, Cravatt BF (2021)
ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth
Nat Chemical Biology
:
Remsberg JR, Suciu RM, Zambetti NA, Hanigan TW, Firestone AJ, Inguva A, Long A, Ngo N, Lum KM, Henry CL, Richardson SK, Predovic M, Huang B, Dix MM, Howell AR, Niphakis MJ, Shannon K, Cravatt BF (2021)
Nat Chemical Biology
: