Involvement of Protrudin mediated ER-endosome contact sites in cancer cell invasion
Cell migration and invasion are processes important for cancer cells to drive metastasis, the ability to invade into the extracellular matrix and to disseminate to distant sites. Cancer cells invade neighboring tissue by protrusions called invadopodia. The spatiotemporal formation and function of invadopodia is tightly regulated and depend on intracellular vesicle transport. Specifically, lysosomes can fuse with the plasma membrane to secrete matrix metalloproteases from invadopodia, thus facilitating invasion.
We have recently identified a mechanism for endosome transport involving the formation of membrane contact sites between the ER and endosomes (Raiborg et al. Nature, 2015). Briefly, ER-localized Protrudin forms contact sites with endosomes by coincident detection of Rab7 and PI3P. Kinesin-1 bound to Protrudin is handed over to FYCO1 on the endosomes, and mediates plus-end-directed movement along microtubules to the cell periphery where the endosomes fuse with the plasma membrane and enables protrusion formation.
We are now in the process of elucidating the potential role of this pathway in the formation and function of invadopodia. Our preliminary results using RPE-1 cells, stably over-expressing Protrudin show by inverted invasion assay and spheroid assay that increasing levels of Protrudin enhances the cells ability to invade into a matrix. Conversely, in MDA-MB231 cells, which are highly invasive breast cancer cells, we find a significant reduced degradation of matrix in a gelatin degradation assay when Protrudin is knocked down by siRNA. In this cell line we detect ER-endosome contact sites, visualized by Protrudin (ER), FYCO1 and Rab7(endosomes), indicating that our newly identified pathway is functional in this cell line. We will further elucidate the potential role and molecular mechanism of the Protrudin-FYCO1 pathway in cancer cell invasion.
Raiborg et al. Nature 2015. Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth.
Published May 29, 2018 2:43 PM
- Last modified May 29, 2018 2:43 PM