Ligand-independent role of ErbB3 in endocytic recycling

Abstract

AbstractActivated receptor tyrosine kinases (RTKs) are important cargo of the endocytic trafficking, yet to what extent RTKs play a role in endocytic trafficking processes per se, remains unclear. Here we show that the ErbB3 receptor, frequently overexpressed in invasive cancers, sorts endocytosed cargo including β1 integrins and the transferrin receptor (TfR) for endocytic recycling in breast epithelial cells, in a manner that does not require ligand-induced ErbB3 signalling. Loss of ErbB3 abrogates recycling of β1 integrins, likely from a Rab4-positive compartment, and redirects it towards lysosomal degradation. Consequently, delivery of β1 integrins to the leading front of migrating sheets of epithelial cells is impaired and collective migration compromised upon loss of ErbB3. Mechanistically, ErbB3 interacts with the endosomal adaptors GGA3 and Rabaptin5 facilitating assembly of an Arf6-GGA3-Rabaptin5 endosomal sorting complex, to promote recycling of cargo such as integrins and TfR. Taken together, our results show that ErbB3 is an integral part of the endosomal trafficking machinery, provoking the notion that RTKs might play yet unrecognised roles in vesicular trafficking.