Loss of ErbB3 redirects Integrin β1 from early endosomal recycling to secretion in extracellular vesicles

Receptor tyrosine kinases (RTKs) are important cargo of endocytic trafficking, yet the role of RTKs in endocytic sorting and maturation of multivesicular bodies (MVBs) per se remains unclear. Here we show that the ErbB3 receptor, frequently overexpressed in invasive breast cancers, sorts internalized transferrin receptor (TfR) and Integrin β1 for endocytic recycling, in a manner that does not require ligand-induced ErbB3 signaling in breast epithelial cells. Loss of ErbB3 abrogates recycling of Integrin β1, likely from a Rab4-positive compartment, and redirects it towards lysosomal degradation or secretion as cargo of extracellular vesicles (EVs). Depletion of ErbB3 impairs migration of sheets of breast epithelial cells, concomitant with imposing a reduction of Integrin β1 cell surface level and an increase in release of EVs containing Integrin β1. In contrast, EVs secreted from ErbB3-depleted cells enhanced the motility of wild-type cells, potentially counteracting the reduced migration of ErbB3-deficient cells. Mechanistically, ErbB3 facilitates assembly of the Arf6-GGA3-Rabaptin5 endosomal sorting complex to promote early recycling, which consequently suppresses EV release. Therefore, ErbB3 constitutes part of the endosomal trafficking machinery, provoking the notion that RTKs might play a novel and yet unrecognised role in vesicular trafficking.