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

Oncogene. 2021 Nov;40(44):6235-6247. doi: 10.1038/s41388-021-02017-8. Epub 2021 Sep 23.


ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cytokines / genetics*
  • Cytokines / metabolism*
  • Endocytosis
  • ErbB Receptors / metabolism
  • Female
  • Gene Knockout Techniques
  • Guanine Nucleotide Dissociation Inhibitors / metabolism*
  • Humans
  • Phosphorylation
  • Prognosis
  • Proteomics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Survival Analysis
  • Ubiquitins / genetics*
  • Ubiquitins / metabolism*


  • Cytokines
  • GDI2 protein, human
  • Guanine Nucleotide Dissociation Inhibitors
  • Ubiquitins
  • ISG15 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt