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RASA2 and NF1; two-negative regulators of Ras with complementary functions in melanoma

Oncogene volume 38, pages 2432–2434 (2019)Cite this article

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Maertens et al. [3] showed that NF1 is specific for KRAS and HRAS in melanoma. To validate this observation in our cells, we overexpressed vector alone (EV) or wild-type NF1 in melanoma cells that harbor RASA2 and NF1 mutations (CO84) and found that wild-type NF1 substantially suppressed KRAS-GTP and HRAS-GTP levels compared to NRAS-GTP levels (Fig. 1B).

As NF1 and RASA2 are RasGAPs and their alterations co-occur, and co-occurring gene alterations in the same tumor are often held to entail synergy, we hypothesized that RASA2 and NF1 may synergize by acting on different RAS isoforms. Indeed, we found that RNAi-mediated suppression of RASA2 led to activation of NRAS-GTP, but not HRAS or KRAS (Fig. 1C and Supplementary Fig. 1A). Conversely, overexpression of wild-type RASA2 substantially suppressed NRAS-GTP, but not KRAS or HRAS, whereas RASA2 mutants failed to do so (Supplementary Fig. 1B, C). Importantly, re-introduction of wild-type RASA2 into melanoma cells harboring RASA2 mutations inhibited NRAS activation (Fig. 1D and Supplementary Table. 1).

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References

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Acknowledgements

We thank T. Wiesel for graphical assistance. This work was supported by the Intramural Research Program of the National Cancer Institute. Y.S. is supported by the Israel Science Foundation grant number 696/17. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation Programme (grant agreement No 754282), the ERC (StG-335377), the Minerva Foundation Grant, the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award, and the Hamburger Family. R.A. is supported by Clore foundation. A.D.P is a Lady Davis postdoctoral fellow.

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Authors and Affiliations

  1. Weizmann Institute of Science, Rehovot, Israel

    Rand Arafeh, Orly Dym & Yardena Samuels

  2. Institute of Biochemistry, Food Science and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel

    Antonella Di Pizio & Masha Y. Niv

  3. National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA

    Abdel G. Elkahloun

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  1. Rand Arafeh
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  2. Antonella Di Pizio
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  3. Abdel G. Elkahloun
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  4. Orly Dym
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  6. Yardena Samuels
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Correspondence to Yardena Samuels.

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Arafeh, R., Di Pizio, A., Elkahloun, A.G. et al. RASA2 and NF1; two-negative regulators of Ras with complementary functions in melanoma. Oncogene 38, 2432–2434 (2019). https://doi.org/10.1038/s41388-018-0578-4

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