The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Canonical RAS signaling primarily involves plasma membrane interactions and PI3K/AKT and RAF/MEK pathways.
• Oncogenic RAS proteins play critical roles in cancer development and progression.
• Nuclear-cytoplasmic transport is essential for cellular function and can be dysregulated in cancer.

Purpose of the Study:

• To identify and characterize a novel, noncanonical oncogenic RAS signaling pathway.
• To elucidate the molecular mechanisms by which RAS promotes nuclear protein export.
• To explore therapeutic strategies targeting this newly identified RAS activity.

Main Methods:

• Investigated RAS•GTP interactions with nuclear export machinery.
• Utilized biochemical assays to study protein complex formation and enzymatic activity.
• Examined the role of XPO1, RanGAP1, EZH2, and DLC1 in RAS-mediated nuclear export.
• Assessed the impact of inhibiting this pathway on tumor suppressor function and cancer cell behavior.

Main Results:

• Identified a noncanonical RAS•GTP activity promoting XPO1-dependent nuclear protein export, independent of PI3K/AKT and RAF/MEK.
• Demonstrated that RAS•GTP forms a perinuclear complex with RanGAP1, facilitating Ran•GTP hydrolysis and nuclear cargo release.
• Showed that export of nuclear EZH2 leads to cytoplasmic degradation of the DLC1 tumor suppressor.
• Found that inhibiting nuclear export enhances the antitumor effects of KRAS inhibition.

Conclusions:

• A novel oncogenic RAS pathway drives cancer progression through enhanced nuclear protein export.
• Targeting this noncanonical RAS activity, potentially by preventing nuclear export, offers a new therapeutic avenue.
• Combining RAS inhibitors with DLC1 reactivation or other cancer treatments may improve therapeutic outcomes.