ArticleHaematologica2009
The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation.
Article in Haematologica, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.Cell metabolism · 2026Article
- Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Genes & diseases · 2024Review
- Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.Science immunology · 2024Article
- PDGFRA K385 mutants in myxoid glioneuronal tumors promote receptor dimerization and oncogenic signaling.Scientific reports · 2024Article
- Novel COL4A1-VEGFD gene fusion in myofibroma.Journal of cellular and molecular medicine · 2021Article
- Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy.Molecules (Basel, Switzerland) · 2021Review
- Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.Cell · 2018Article
- Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis.Leukemia · 2018Article
- Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities.Cancer science · 2017Article
- Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling.Journal of cellular and molecular medicine · 2015Article
- Novel targeted therapies for eosinophil-associated diseases and allergy.Annual review of pharmacology and toxicology · 2015Review
- The oncogenic FIP1L1-PDGFRα fusion protein displays skewed signaling properties compared to its wild-type PDGFRα counterpart.JAK-STAT · 2015Article
- Article
- The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V.Molecular oncology · 2014Article
- Targeting the PDGF signaling pathway in tumor treatment.Cell communication and signaling : CCS · 2013Review
- STAT5 acetylation: Mechanisms and consequences for immunological control and leukemogenesis.JAK-STAT · 2013Review
- Review of current classification, molecular alterations, and tyrosine kinase inhibitor therapies in myeloproliferative disorders with hypereosinophilia.Journal of blood medicine · 2013Article
- ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB.Haematologica · 2012Article
- The leukemia-associated fusion protein Tel-platelet-derived growth factor receptor β (Tel-PdgfRβ) inhibits transcriptional repression of PTPN13 gene by interferon consensus sequence binding protein (Icsbp).The Journal of biological chemistry · 2012Article
- Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.Journal of cellular and molecular medicine · 2012Review
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundChimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRalpha (FPalpha) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. DESIGN AND
methodsWe used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation.
resultsIn contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPbeta, FPalpha and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPbeta and FPalpha hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPbeta and FPalpha was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPbeta induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPbeta reduced cell transformation and STAT5 activation.
conclusionsWe have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.
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