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04:47
Measuring Transcellular Interactions through Protein Aggregation in a Heterologous Cell System
Published on: May 22, 2020
Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling.
A B Hanker1, N Mitin, R S Wilder
1Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Oncogene
|October 20, 2009
Summary
Post-translational modifications like farnesylation, Rce1 cleavage, and Icmt methylation are essential for Rheb GTPase localization but not for mTOR signaling activation. Farnesylthiosalicylic acid (FTS) inhibits mTOR downstream of Rheb, offering potential cancer therapy.
Area of Science:
- Molecular biology
- Cellular signaling
- Cancer research
Background:
- Rheb1 and Rheb2 GTPases and their effector mTOR are implicated in human cancers.
- Rheb localization to endomembranes depends on its C-terminal CAAX motif and posttranslational modifications.
Purpose of the Study:
- To investigate the role of postprenylation processing (Rce1 and Icmt) in Rheb localization and mTOR signaling.
- To determine if farnesylthiosalicylic acid (FTS) inhibits Rheb function and explore its potential as an anti-cancer therapeutic.
Main Methods:
- Studied Rheb1 and Rheb2 localization in endoplasmic reticulum and Golgi apparatus.
- Assessed the requirement of Icmt and Rce1 for Rheb localization and mTOR substrate p70 S6 kinase (S6K) activation.
- Evaluated the effect of FTS on Rheb localization and S6K activation.
Main Results:
- Icmt and Rce1 processing are necessary for Rheb localization but dispensable for Rheb-induced S6K activation.
- FTS treatment inhibited S6K activation by a constitutively active mTOR mutant, indicating FTS acts downstream of Rheb.
- FTS demonstrated potential as a therapeutic agent for Rheb- and mTOR-dependent cancers.
Conclusions:
- Inhibitors of Icmt and Rce1 are unlikely to block Rheb function.
- FTS shows promise as a novel therapeutic strategy for cancers driven by Rheb and mTOR signaling pathways.
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