ArticlePloS one2011
The von Hippel-Lindau tumor suppressor protein promotes c-Cbl-independent poly-ubiquitylation and degradation of the activated EGFR.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 53 citations in OpenAlex.
- Beyond hypoxia and ccRCC: the expanding universe of VHL novel targets and next-generation therapeutics.Biomarker research · 2026Review
- Von Hippel-Lindau/Hypoxia Inducible Factor Axis in Glioblastoma.International journal of molecular sciences · 2025Review
- Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma.Cell death & disease · 2025Article
- SOCS domain targets ECM assembly in lung fibroblasts and experimental lung fibrosis.Scientific reports · 2024Article
- SOCS domain targets ECM assembly in lung fibroblasts and experimental lung fibrosis.bioRxiv : the preprint server for biology · 2024Article
- Neddylation of protein, a new strategy of protein post-translational modification for targeted treatment of central nervous system diseases.Frontiers in neuroscience · 2024Review
- Dysregulation of ubiquitination modification in renal cell carcinoma.Frontiers in genetics · 2024Review
- The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies.Frontiers in pharmacology · 2024Review
- von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology.Hematology/oncology clinics of North America · 2023Review
- Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance.Cancers · 2023Review
- Genetic and Epigenetic Mechanisms Deregulate the CRL2Frontiers in genetics · 2022Article
- Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation.Molecules (Basel, Switzerland) · 2021Review
- PARK7 maintains the stemness of glioblastoma stem cells by stabilizing epidermal growth factor receptor variant III.Oncogene · 2021Article
- Ubiquitin ligase SMURF2 enhances epidermal growth factor receptor stability and tyrosine-kinase inhibitor resistance.The Journal of biological chemistry · 2020Article
- Differential behavior of NF-κB, IκBα and EGFR during the renal carcinogenic process in an experimental modelOncology letters · 2020Article
- Overexpression of EGFR and TGFα in von Hippel-Lindau-Related Central Nervous System Hemangioblastomas.Frontiers in oncology · 2020Article
- The RNA polymerase III repressor MAF1 is regulated by ubiquitin-dependent proteasome degradation and modulates cancer drug resistance and apoptosis.The Journal of biological chemistry · 2019Article
- VHL and Hypoxia Signaling: Beyond HIF in Cancer.Biomedicines · 2018Review
- Hypoxia-Inducible Factor 2-Dependent Pathways Driving Von Hippel-Lindau-Deficient Renal Cancer.Frontiers in oncology · 2018Review
- Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.Oncogene · 2017Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Somatic mutations or reduced expression of the von Hippel-Lindau (VHL) tumor suppressor occurs in the majority of the clear cell renal cell carcinoma (ccRCC) and is a causal factor for the pathogenesis of ccRCC. pVHL was reported to suppress the oncogenic activity of Epidermal Growth Factor Receptor (EGFR) by reducing the expression of the EGFR agonist TGF-α and by reducing the translation efficiency of EGFR itself. Furthermore, it was reported that pVHL down-regulates activated EGFR by promoting efficient lysosomal degradation of the receptor. These modes of negative regulation of EGFR by pVHL were dependent on Hypoxia Inducible Factor (HIF). In this study, we report that HIF was not the only factor stabilizing the activated EGFR in VHL-deficient ccRCC cells. Down-regulation of endogenous HIF in these cells had little effect on the turnover rates of the activated EGFR. Furthermore, neither pretreatment with lysosomal inhibitors pretreatment nor down-regulation of c-Cbl, a major E3 ubiquitin ligase that targets the activated EGFR for lysosomal degradation, significantly increased the stabilities of EGFR in VHL-expressing ccRCC cells. In contrast, pretreatment with proteasomal inhibitors extended EGFR lifetime and led to similar EGFR half-lives in VHL-expressing and VHL-deficient ccRCC cells. Down-regulation of c-Cbl in VHL-deficient ccRCC cells revealed that the c-Cbl and pVHL collaborated to down-regulate the activated EGFR. Finally, we found that pVHL promoted the poly-ubiquitylation of the activated EGFR, and this function was c-Cbl-independent. Thus these results indicate that pVHL limits EGFR signaling by promoting c-Cbl-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome.
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