E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK–CBL–CIN85 axis
Open Access
- 24 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (12), 2149-2164
- https://doi.org/10.1038/s41388-021-01684-x
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.Keywords
This publication has 56 references indexed in Scilit:
- CIN85 phosphorylation is essential for EGFR ubiquitination and sorting into multivesicular bodiesMolecular Biology of the Cell, 2012
- Novel Oncogenic Mutations of CBL in Human Acute Myeloid Leukemia That Activate Growth and Survival Pathways Depend on Increased MetabolismJournal of Biological Chemistry, 2010
- A Dyn2–CIN85 complex mediates degradative traffic of the EGFR by regulation of late endosomal buddingThe EMBO Journal, 2010
- Cbl and Human Myeloid Neoplasms: The Cbl Oncogene Comes of AgeCancer Research, 2010
- Cbl Controls EGFR Fate by Regulating Early Endosome FusionScience Signaling, 2009
- TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancerBritish Journal of Cancer, 2008
- Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substratesThe EMBO Journal, 2008
- Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemiaBlood, 2007
- CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machineryThe EMBO Journal, 2007
- The COSMIC (Catalogue of Somatic Mutations in Cancer) database and websiteBritish Journal of Cancer, 2004