TY - JOUR
T1 - USP17 Regulates Ras Activation and Cell Proliferation by Blocking RCE1 Activity
AU - Burrows, James F.
AU - Kelvin, Alyson A.
AU - McFarlane, Cheryl
AU - Burden, Roberta E.
AU - McGrattan, Michael J.
AU - De la Vega, Michelle
AU - Govender, Ureshnie
AU - Quinn, Derek J.
AU - Dib, Karim
AU - Gadina, Massimo
AU - Scott, Christopher J.
AU - Johnston, James A.
PY - 2009/4/3
Y1 - 2009/4/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=66149093056&partnerID=8YFLogxK
U2 - 10.1074/jbc.M807216200
DO - 10.1074/jbc.M807216200
M3 - Article
VL - 284
SP - 9587
EP - 9595
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 14
ER -