Abstract 3782: NEDD9 promotes cell invasion through modulation of Arf6-dependent endocytic recycling.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The adaptor protein, NEDD9, is an established pro-metastatic trigger in several cancers but the molecular mechanisms behind NEDD9-driven invasion remain unclear. Here we show that expression of NEDD9 protein tightly correlates with the transition of breast cancer to invasive stages. Overexpression of NEDD9 is critical for the invasion of cancer cells but depletion of NEDD9 is sufficient to block invasion. It is also well established that invadopodia are important for cell invasion. We demonstrate that NEDD9 localizes to invadopodia and its depletion leads to a deficiency in matrix degradation. NEDD9 depletion was also accompanied by an increase in surface levels of inactive proteases (MT1-MMP) and adhesion receptors (integrins). In addition, depletion of NEDD9 induced an increase in recycling and early endosomes via activation of Arf6. NEDD9 binds to the Arf6 specific GAP, ASAP3, which explains NEDD9 modulation of Arf6 activity. Inhibition of Arf6 or re-expression of NEDD9 rescue in NEDD9-deficient cells is sufficient to restore proper recycling rates and invasive properties of breast cancer cells. These results reveal the mechanism behind NEDD9-driven migration and tumor invasion. Citation Format: Yuriy Loskutov, Sarah McLaughlin, Polina Kozyulina, Varvara Kozyreva, Ryan Ice, Anuradha Rajulapati, Mark Culp, Robert Wysolmerski, Alexey Ivanov, Scott Weed, Elena Pugacheva. NEDD9 promotes cell invasion through modulation of Arf6-dependent endocytic recycling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3782. doi:10.1158/1538-7445.AM2013-3782