ArticleThe Journal of biological chemistry2016
The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor β (PDGFRβ) Internalization and Signaling.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A PDGFRB-CD44-MIF crosstalk promotes cancer-associated cellular phenotypes in ATRT-TYR/MYC cell lines.Frontiers in oncology · 2026Article
- Targeted Protein Degradation in Lung Cancer: The Emerging Role of PROTAC Technology and E3 Ligases.Current medicinal chemistry · 2026Review
- Novel combination therapy with phenformin enhances the effects of lenvatinib in hepatocellular carcinoma via AMPK-mediated PDGFRβ degradation.Cancer cell international · 2025Article
- New insights into the role of ubiquitination in angiogenesis (Review).International journal of molecular medicine · 2025Review
- PTPN14 aggravates neointimal hyperplasia via boosting PDGFRβ signaling in smooth muscle cells.Nature communications · 2024Article
- Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ.Frontiers of medicine · 2024Article
- Differentially expressed platelet activation-related genes in dogs with stage B2 myxomatous mitral valve disease.BMC veterinary research · 2023Article
- Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes.Molecular biology of the cell · 2023Article
- Review
- Article
- SUMOylation of PDGF receptor α affects signaling via PLCγ and STAT3, and cell proliferation.BMC molecular and cell biology · 2023Article
- The E3 Ubiquitin Ligase TRIM21 Regulates Basal Levels of PDGFRβ.International journal of molecular sciences · 2023Article
- PDGFR dimer-specific activation, trafficking and downstream signaling dynamics.Journal of cell science · 2022Article
- E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR.The Journal of biological chemistry · 2022Article
- Deubiquitinating enzymes USP4 and USP17 finetune the trafficking of PDGFRβ and affect PDGF-BB-induced STAT3 signalling.Cellular and molecular life sciences : CMLS · 2022Article
- Negative regulation of receptor tyrosine kinases by ubiquitination: Key roles of the Cbl family of E3 ubiquitin ligases.Frontiers in endocrinology · 2022Review
- Proteomic investigation of Cbl and Cbl-b in neuroblastoma cell differentiation highlights roles for SHP-2 and CDK16.iScience · 2021Article
- The emerging complexity of PDGFRs: activation, internalization and signal attenuation.Biochemical Society transactions · 2020Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein ubiquitination controls protein stability and subcellular localization of tyrosine kinase receptors, hence affecting signaling both quantitatively and qualitatively. In this report, we demonstrate that, after ligand stimulation, the PDGF β receptor (PDGFRβ) becomes ubiquitinated in a manner requiring both the c-Cbl and Cbl-b ubiquitin ligases. Simultaneous depletion of c-Cbl and Cbl-b resulted in reduced ligand-induced PDGFRβ clearance from the cell surface because of reduced endocytosis of the receptor. Cbl-b formed a complex with c-Cbl, as well as with the PDGFRβ, in response to PDGF-BB stimulation. We were unable to find a direct interaction between the receptor and c-Cbl, raising the possibility that Cbl-b is necessary for c-Cbl to interact with PDGFRβ. Phosphorylated Tyr-1021 in PDGFRβ was the primary interaction site for Cbl-b, with some contribution from Tyr-1009. Depletion of c-Cbl and Cbl-b led to an increased ligand-induced tyrosine phosphorylation of the receptor. Several tyrosine residues with elevated phosphorylation (i.e. Tyr-579, Tyr-581, Tyr-1009, and Tyr-1021) have previously been shown to interact with Src kinases and PLCγ. Indeed, in cells depleted of c-Cbl and Cbl-b, both Src and PLCγ phosphorylation were enhanced, whereas activation of other pathways, such as Erk1/2 MAP kinase and Akt, were not affected. In addition, Stat3 phosphorylation, which has been connected to Src activity, was also elevated in cells lacking c-Cbl and Cbl-b. Functionally, we found that cells depleted of c-Cbl and Cbl-b were more prone to migrate toward PDGF-BB, whereas no reproducible effect on cell proliferation could be observed. In conclusion, internalization as well as signaling via PDGFRβ are controlled by ubiquitination.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.