The endoplasmic-reticulum-associated degradation (ERAD) pathway targets correctly folded and misfolded physiological substrates for ubiquitylation and subsequent degradation by the proteasome. Gp78 is a cell-surface receptor that also functions as an E3 ubiquitin ligase in ERAD. The Gp78 ligand is the glycolytic enzyme phosphoglucose isomerase PGI (also known as AMF), a cytokine that is secreted by tumour cells, stimulating their motility and proliferation through activation of the small GTPases RhoA and Rac1. Gp78 internalises AMF through a dynamin- and phosphatidylinositide 3-kinase-dependent raft-mediated endocytic pathway to the smooth ER; but the functional relationship between AMF and the ubiquitin ligase activity of Gp78 remains unclear. Here, (p. 3295), Ivan Robert Nabi and colleagues show that raft-dependent Gp78-mediated endocytosis of AMF depends on Rac1 and not RhoA, which suggests that AMF uptake defines a distinct raft endocytosis pathway. In addition, uptake of AMF enhances Rac1 activation – which, in turn, further increases its internalisation – indicating a positive feedback loop to promote AMF endocytosis. Furthermore, the authors show that AMF uptake prevents Gp78-induced degradation of mitofusins and Gp78-mediated mitochondrial fission. Taken together, these data point to a new mechanism, whereby the regulation of a key component of the ERAD pathway through an extracellular ligand contributes to Gp78 promotion of cell motility and tumour metastasis.