Rab14 and Its Exchange Factor FAM116 Link Endocytic Recycling and Adherens Junction Stability in Migrating Cells

Summary

Rab GTPases define the vesicle trafficking pathways underpinning cell polarization and migration. 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. Rab14 and its GEF FAM116A localize 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 accumulates in a transferrin-positive endocytic compartment, and the cell-surface level of ADAM10 is correspondingly reduced. FAM116 and Rab14 therefore define an endocytic recycling pathway needed for ADAM protease trafficking and regulation of cell-cell junctions.

Abstract

Graphical Abstract

Highlights

► FAM116A is a GDP-GTP exchange factor for the GTPase Rab14 ► Rab14 defines an endocytic recycling pathway required for ADAM10 transport ► In Rab14-depleted cells, ADAM10 fails to degrade its substrate, N-cadherin ► Dysregulation of ADAM10/N-cadherin accounts for Rab14 effects on cell migration

Abstract

Linford et al. show that Rab14 and its exchange factor FAM116 are required for the endocytic recycling of the ADAM10 protease. In cells lacking Rab14 or FAM116, ADAM10 is mislocalized and cannot process its substrate N-cadherin. This leads to stabilization of the adherens junctions and thereby interferes with cell migration.