ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

ABSTRACT ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. However, the mechanism by which ISG15 achieves this remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR). By regulating EGFR trafficking, ISGylation sustains Akt-signalling in vitro and in vivo . Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in animal models and human breast cancers. We show that ISGylation can act as driver of tumour progression rather than merely being a marker of it.