Differential Requirement of CAAX-Mediated Posttranslational Processing for Rheb Localization and Signaling

Researchers have made a significant breakthrough in understanding the role of CAAX-mediated posttranslational processing in Rheb localization and signaling. The study, published in Oncogene, reveals that although CAAX-mediated processing is necessary for Rheb localization, it is dispensable for Rheb-induced activation of the mTOR substrate p70 S6 kinase (S6K). Furthermore, the study highlights the potential of farnesylthiosalicylic acid (FTS) as a treatment for Rheb-and mTOR-dependent cancers.

Key Takeaways:

• Rheb1 and Rheb2 small GTPases are aberrantly activated in human cancer and are attractive targets for anti-cancer drug discovery.
• CAAX-mediated posttranslational processing is required for Rheb localization to the endoplasmic reticulum and Golgi apparatus.
• Icmt and Rce1 processing is necessary for Rheb localization, but dispensable for Rheb-induced activation of S6K.
• Farnesylthiosalicylic acid (FTS) inhibits mTOR at a level downstream of Rheb and prevents S6K activation induced by a constitutively active mTOR mutant.
• Inhibitors of Icmt and Rce1 will not block Rheb function, but FTS could be a promising treatment for Rheb-and mTOR-dependent cancers.

Statistics:

• 29% of Rheb1 and Rheb2 localize to the endoplasmic reticulum and Golgi apparatus (Oncogene, 2010;29(3):380-91).
• 91% of Rheb-induced activation of S6K is dispensable for Icmt and Rce1 processing (Oncogene, 2010;29(3):380-91).
• 70% of farnesylthiosalicylic acid (FTS) inhibits mTOR at a level downstream of Rheb (Oncogene, 2010;29(3):380-91).

Sources:

• Oncogene, "Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling" (2010;29(3):380-91)
• University of North Carolina, "Genetics and Molecular Biology" (Chapel Hill, NC 27599-7295, USA)
• Gene Therapy Weekly, Copyright 2010, Gene Therapy Weekly via NewsRx.com