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

• Published in: Nature communications 2019-06, Vol.10 (1), p.2666-12, Article 2666
• Main Authors: Zaoui, Kossay, Boudhraa, Zied, Khalifé, Paul, Carmona, Euridice, Provencher, Diane, Mes-Masson, Anne-Marie
• Format: Article
• Language: English
• Subjects: 13/106; 13/89; 13/95; 14/19; 45/70; 49/109; 631/67/1517/1709; 631/67/322; 82/80; 96/35; Cancer; Carcinoma, Ovarian Epithelial - pathology; Cell cycle; Cell Line, Tumor; Cell Membrane - metabolism; Cell survival; Depletion; Drug development; Female; Gene Knockdown Techniques; Guanosine triphosphatases; Humanities and Social Sciences; Humans; Localization; Metastases; Mode of action; multidisciplinary; Neoplasm Invasiveness - pathology; Ovarian cancer; Ovarian Neoplasms - pathology; Proteasomes; Protein Domains; Protein Stability; Proteolysis; ran GTP-Binding Protein - genetics; ran GTP-Binding Protein - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; Science; Science (multidisciplinary); Serine; Serine - metabolism; Signal Transduction; Signaling; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10570-w

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. Ran, a nucleus-cytoplasm shuttle protein, is implicated in cancer development and survival. Here, the authors show that Ran binds RhoA to impair its degradation and allow its localisation to the plasma membrane of ovarian cancer cells for tumour invasion.