E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK–CBL–CIN85 axis

Ahmed, S. F., Buetow, L., Gabrielsen, M. , Lilla, S., Sibbet, G. J., Sumpton, D., Zanivan, S. , Hedley, A., Clark, W. and Huang, D. T. (2021) E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK–CBL–CIN85 axis. Oncogene, 40(12), pp. 2149-2164. (doi: 10.1038/s41388-021-01684-x) (PMID:33627783) (PMCID:PMC7994203)

Abstract

Casitas B-lineage lymphoma (CBL) is a ubiquitin ligase (E3) that becomes activated upon Tyr371-phosphorylation and targets receptor protein tyrosine kinases for ubiquitin-mediated degradation. Deregulation of CBL and its E3 activity is observed in myeloproliferative neoplasms and other cancers, including breast, colon, and prostate cancer. Here, we explore the oncogenic mechanism of E3-inactive CBL mutants identified in myeloproliferative neoplasms. We show that these mutants bind strongly to CIN85 under normal growth conditions and alter the CBL interactome. Lack of E3 activity deregulates CIN85 endosomal trafficking, leading to an altered transcriptome that amplifies signaling events to promote oncogenesis. Disruption of CBL mutant interactions with EGFR or CIN85 reduces oncogenic transformation. Given the importance of the CBL–CIN85 interaction in breast cancers, we examined the expression levels of CIN85, CBL, and the status of Tyr371-phosphorylated CBL (pCBL) in human breast cancer tissue microarrays. Interestingly, pCBL shows an inverse correlation with both CIN85 and CBL, suggesting that high expression of inactivated CBL could coordinate with CIN85 for breast cancer progression. Inhibition of the CBL–CIN85 interaction with a proline-rich peptide of CBL that binds CIN85 reduced the proliferation of MDA-MB-231 cells. Together, these results provide a rationale for exploring the potential of targeting the EGFR–CBL–CIN85 axis in CBL-inactivated mutant cancers.

• Item Type: Articles
• Additional Information: This work was supported by the Beatson Institute’s Cancer Research UK core funding (A17196), Cancer research UK (A23278/A29256) to D.T.H. and (C596/A12935) to S.Z., and European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement n° 647849) to D.T.H. We thank Catherine Winchester for assistance in critically reviewing this manuscript and Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to Proteomics, Histology and Molecular Technologies services.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sumpton, Mr David and Lilla, Dr Sergio and Huang, Professor Danny and Gabrielsen, Dr Mads and Sibbet, Dr Gary and Clark, Mr William and Zanivan, Professor Sara and Buetow, Dr Lori
• Authors: Ahmed, S. F., Buetow, L., Gabrielsen, M., Lilla, S., Sibbet, G. J., Sumpton, D., Zanivan, S., Hedley, A., Clark, W., and Huang, D. T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Oncogene
• Publisher: Springer Nature
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 24 February 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Oncogene 40(12): 2149-2164
• Publisher Policy: Reproduced under a Creative Commons license