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

Brajendra K Tripathi1, Nicole H Hirsh2, Xiaolan Qian2

  • 1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. tripathib@mail.nih.gov.

Nature Cancer
|November 11, 2024
PubMed

Insights

Researchers discovered a new oncogenic RAS signaling pathway that moves nuclear proteins to the cytoplasm, independent of PI3K/AKT and RAF/MEK. This pathway involves RAS•GTP, XPO1, and RanGAP1, promoting cancer by degrading tumor suppressors like DLC1.

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.

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