scholarly journals ABHD17 enzymes regulate dynamic plasma membrane palmitoylation and N-Ras-dependent cancer growth

Author(s):  
Jarrett R. Remsberg ◽  
Radu M. Suciu ◽  
Noemi A. Zambetti ◽  
Thomas W. Hanigan ◽  
Ari J. Firestone ◽  
...  

A subset of 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 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 to Palmostatin 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 MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

2015 ◽  
Vol 43 (7) ◽  
pp. 524-533.e1 ◽  
Author(s):  
Ichiro Kawashima ◽  
Toru Mitsumori ◽  
Yumi Nozaki ◽  
Takeo Yamamoto ◽  
Yuki Shobu-Sueki ◽  
...  

2015 ◽  
Vol 5 (3) ◽  
pp. e297-e297 ◽  
Author(s):  
E Saland ◽  
H Boutzen ◽  
R Castellano ◽  
L Pouyet ◽  
E Griessinger ◽  
...  

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