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Rab GTPases define the vesicle trafficking pathways underpinning cell polarisation and migration. However, it remains unclear how Rabs crucial for cell migration and polarisation are regulated. Here, we find that Rab4, Rab11, and Rab14 and the candidate Rab GDP-GTP exchange factors (GEFs) FAM116A and AVL9 are required for cell migration. GEF assays using purified proteins reveal that FAM116 proteins have nucleotide exchange factor activity towards Rab14. Accordingly, Rab14 and FAM116A localise to and act on an intermediate compartment of the transferrin-recycling pathway prior to Rab11 and after Rab5 and Rab4. This Rab14 intermediate recycling compartment has specific functions in migrating cells discrete from early and recycling endosomes. Rab14 depleted cells show increased N-cadherin levels at junctional complexes, and cannot resolve cell-cell junctions. This is due to decreased shedding of cell-surface N-cadherin by the ADAM family protease ADAM10/Kuzbanian. In FAM116A and Rab14 depleted cells, ADAM10 levels at the cell surface are reduced and it accumulates in a transferrin-positive endocytic compartment. FAM116 and Rab14 therefore define a novel endocytic-recycling pathway needed for ADAM protease trafficking and regulation of cell-cell junctions.


Journal article


Developmental Cell