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

Alfonso Bolado-carrancio, Martin Lee, Ailith Ewing, Morwenna Muir, Kenneth G. Macleod, William M. Gallagher, Lan K. Nguyen, Neil O. Carragher, Colin A. Semple, Valerie G. Brunton, Patrick T. Caswell, Alex Von Kriegsheim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
JournalOncogene
Early online date23 Sep 2021
DOIs
Publication statusE-pub ahead of print - 23 Sep 2021

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