The identification of Rab GTPase Control Systems involved in cell migration

Rab GTPases are known to define the vesicle trafficking pathways that underpin cell polarisation and migration. In this study it was demonstrated that Rab4, Rab11, Rab14 and the candidate Rab GDP-GTP exchange factor (GEF) FAM116A are all required for cell migration. This work also demonstrates that Rab14 and its GEF FAM116A localise to and act on an intermediate compartment within the transferrin recycling pathway acting upstream of Rab11 and downstream of Rab5. Further analysis revealed that a Rab14-dependent intermediate recycling compartment that is discrete from early and recycling endosomes, has an important function for cargo sorting in migrating cells. Cells depleted of Rab14 show increased levels of N-cadherin at junctional complexes and these cell-cell adhesions are unable to be resolved preventing cell migration. This results from decreased shedding of Ncadherin at the cell surface that is usually cleaved by A Disintegrin and Metalloprotease (ADAM) family protease ADAM10. In FAM116A- and Rab14-depleted cells, ADAM10 is trapped and therefore accumulates in a transferrin-positive endocytic compartment, and the cell-surface level of ADAM10 is correspondingly reduced. Rab14 and its GEF FAM116A define an endocytic-recycling pathway that is essential for the trafficking of ADAM10 and therefore in turn regulate cell-cell junctions and cell migration