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USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity
James F Burrows1, Alyson A Kelvin, Cheryl McFarlane
1Division 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.
The Journal of Biological Chemistry
|February 4, 2009
Summary
The deubiquitinating enzyme USP17 inhibits Ras protein activation by deactivating Ras-converting enzyme 1 (RCE1). This blocks Ras membrane localization and downstream signaling, impacting cell growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Proto-oncogene Ras requires post-translational modifications for membrane localization and function.
- Cleavage of the Ras CAAX motif by Ras-converting enzyme 1 (RCE1) is a critical modification step.
Purpose of the Study:
- To investigate the role of the deubiquitinating enzyme USP17 in regulating Ras processing and activation.
- To elucidate the mechanism by which USP17 affects RCE1 activity and downstream signaling.
Main Methods:
- Assessing Ras membrane localization and activation via Western blotting.
- Measuring phosphorylation of downstream kinases MEK and ERK.
- Co-localization studies of USP17 and RCE1 at the endoplasmic reticulum.
- Experiments in RCE1-null cells to confirm USP17's mechanism.
Main Results:
- USP17 expression inhibits Ras membrane localization and activation.
- USP17 blocks phosphorylation of MEK and ERK.
- USP17 deubiquitinates and inactivates RCE1, leading to these effects.
- USP17 and RCE1 co-localize at the endoplasmic reticulum.
- USP17's inhibitory effects are absent in RCE1-null cells.
Conclusions:
- USP17 negatively regulates RCE1 activity through deubiquitination.
- USP17 modulates Ras processing and activation by controlling RCE1 function.
- This mechanism impacts Ras-driven signaling pathways and cellular proliferation.
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