Small-molecule inhibition of APT1 affects Ras localization and signaling.
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.
Dekker
Frank J
FJ
Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany.
Rocks
Oliver
O
Vartak
Nachiket
N
Menninger
Sascha
S
Hedberg
Christian
C
Balamurugan
Rengarajan
R
Wetzel
Stefan
S
Renner
Steffen
S
Gerauer
Marc
M
Schölermann
Beate
B
Rusch
Marion
M
Kramer
John W
JW
Rauh
Daniel
D
Coates
Geoffrey W
GW
Brunsveld
Luc
L
Bastiaens
Philippe I H
PI
Waldmann
Herbert
H
D000818:Animals; D002460:Cell Line; D004285:Dogs; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008049:Lipase / Q000737:chemistry / Q000378:metabolism; D054878:Lipoylation / Q000187:drug effects; D008958:Models, Molecular; D011420:Propiolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction; D013270:Stomach / Q000201:enzymology; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D004791:Enzyme Inhibitors; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C578782:palmostatin B; D011420:Propiolactone; D008049:Lipase; C402226:LYPLA1 protein, human; D013869:Thiolester Hydrolases; D018631:ras Proteins