Journal
ONCOGENE
Volume 40, Issue 44, Pages 6235-6247Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-02017-8
Keywords
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Funding
- Breast Cancer NOW [2013NovPR183]
- Cancer Research UK (CRUK) [C157/A255140, C157/A24837]
- Wellcome Trust [208402/Z/17/Z, 203128/A/16/Z]
- MRC [MC_UU_00007/16, MR/R009376/1]
- Worldwide Cancer Research [14-1226]
- Australia's Victorian Cancer Agency [MCRF18026]
- BREAST-PREDICT (CCRC13GAL)
- Science Foundation Ireland [15/IA/3104]
- Wellcome Trust [203128/A/16/Z] Funding Source: Wellcome Trust
- MRC [MR/R009376/1] Funding Source: UKRI
- Medical Research Council [MC_UU_00007/16, MR/R009376/1] Funding Source: researchfish
- Worldwide Cancer Research [14-1226] Funding Source: researchfish
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ISG15 modifies GDI2 through ISGylation to alter EGFR trafficking, enhance Akt signaling, and drive more aggressive tumor behavior in human breast cancer.
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.
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