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

Canonical RAS signaling, including PI3K/AKT- and RAF/MEK-dependent activities, results mainly from RAS•GTP interaction with its effectors at the plasma membrane. Here, we identified a fundamental, oncogenic, noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear protein cargo into the cytoplasm and is independent of PI3K/AKT and RAF/MEK signaling. This RAS-dependent step acts downstream from XPO1 binding to nuclear protein cargo and is mediated by a perinuclear protein complex between RAS•GTP and RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP, which promotes release of nuclear protein cargo into the cytoplasm. The export of nuclear EZH2, which promotes cytoplasmic degradation of the DLC1 tumor suppressor protein, is a biologically important component of this pro-oncogenic activity. Conversely, preventing nuclear protein export contributes to the antitumor activity of KRAS inhibition, which can be further augmented by reactivating the tumor suppressor activity of DLC1 or potentially combining RAS inhibitors with other cancer treatments.

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Publication Details

Journal
Nature Cancer
Published
2024-11-11
DOI
https://doi.org/10.1038/s43018-024-00847-5
Citations
9
Primary Topic
Nuclear Structure and Function
Type
article
Field-Weighted Citation Impact
2.10
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article

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

James H. Doroshow, Ross Lake, Yvonne A. Evrard, Mary Dasso et al.
9 citations
Nature Cancer
Nuclear Structure and Function
2.10
article

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

James H. Doroshow, Ross Lake, Yvonne A. Evrard, Mary Dasso, Brajendra K. Tripathi, Dunrui Wang, Kylie J. Walters, Nicole H. Hirsh, Adam I. Marcus, Marian E. Durkin, Douglas R. Lowy, Suresh S. Ramalingam, Karen H. Vousden, Xiaolan Qian, Alex G. Papageorge
article en
9 citations

Abstract

Canonical RAS signaling, including PI3K/AKT- and RAF/MEK-dependent activities, results mainly from RAS•GTP interaction with its effectors at the plasma membrane. Here, we identified a fundamental, oncogenic, noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear protein cargo into the cytoplasm and is independent of PI3K/AKT and RAF/MEK signaling. This RAS-dependent step acts downstream from XPO1 binding to nuclear protein cargo and is mediated by a perinuclear protein complex between RAS•GTP and RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP, which promotes release of nuclear protein cargo into the cytoplasm. The export of nuclear EZH2, which promotes cytoplasmic degradation of the DLC1 tumor suppressor protein, is a biologically important component of this pro-oncogenic activity. Conversely, preventing nuclear protein export contributes to the antitumor activity of KRAS inhibition, which can be further augmented by reactivating the tumor suppressor activity of DLC1 or potentially combining RAS inhibitors with other cancer treatments.

Nature CancerVol. 5(12)
Leidos (United States) (US), National Institutes of Health (US), Emory University (US), The Francis Crick Institute (GB), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), Center for Cancer Research (US)
Decent work and economic growth
Openalex Percentile: Top 12%
Nuclear Structure and Function
2.10
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