USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity.
The proto-oncogene Ras undergoes a series of post-translational modifications at its carboxyl-terminal CAAX motif that are essential for its proper membrane localization and function. One step in this process is the cleavage of the CAAX motif by the enzyme Ras-converting enzyme 1 (RCE1). Here we show that the deubiquitinating enzyme USP17 negatively regulates the activity of RCE1. We demonstrate that USP17 expression blocks Ras membrane localization and activation, thereby inhibiting phosphorylation of the downstream kinases MEK and ERK. Furthermore, we show that this effect is caused by the loss of RCE1 catalytic activity as a result of its deubiquitination by USP17. We also show that USP17 and RCE1 co-localize at the endoplasmic reticulum and that USP17 cannot block proliferation or Ras membrane localization in RCE1 null cells. These studies demonstrate that USP17 modulates Ras processing and activation, at least in part, by regulating RCE1 activity.
Burrows
James F
JF
Division of Infection and Immunity, Centre for Cancer Research and Cell Biology, School of Biomedical Sciences, Queen's University Belfast, University Road, Belfast BT7 1NN, Northern Ireland.
Kelvin
Alyson A
AA
McFarlane
Cheryl
C
Burden
Roberta E
RE
McGrattan
Michael J
MJ
De la Vega
Michelle
M
Govender
Ureshnie
U
Quinn
Derek J
DJ
Dib
Karim
K
Gadina
Massimo
M
Scott
Christopher J
CJ
Johnston
James A
JA
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases; C491324:Rce1 protein, mouse; D018631:ras Proteins