Ran promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion

Kossay Zaoui, Zied Boudhraa, Paul Khalifé, Euridice Carmona, Diane Provencher and Anne-Marie Mes-Masson ()
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Kossay Zaoui: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Zied Boudhraa: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Paul Khalifé: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Euridice Carmona: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Diane Provencher: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Anne-Marie Mes-Masson: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclear-cytoplasmic transport, and cell transformation. Ran plays an important role in cancer cell survival and cancer progression. Here, we show that, in addition to the nucleocytoplasmic localization of Ran, this GTPase is specifically associated with the plasma membrane/ruffles of ovarian cancer cells. Ran depletion has a drastic effect on RhoA stability and inhibits RhoA localization to the plasma membrane/ruffles and RhoA activity. We further demonstrate that the DEDDDL domain of Ran is required for the interaction with serine 188 of RhoA, which prevents RhoA degradation by the proteasome pathway. Moreover, the knockdown of Ran leads to a reduction of ovarian cancer cell invasion by impairing RhoA signalling. Our findings provide advanced insights into the mode of action of the Ran-RhoA signalling axis and may represent a potential therapeutic avenue for drug development to prevent ovarian tumour metastasis.

Date: 2019
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DOI: 10.1038/s41467-019-10570-w

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