ArticleBlood2013
Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis.
Article in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Evaluating Transcriptomic Biomarkers for rHuEPO Detection: Assessing the Impact of Exercise and Altitude Exposure.Drug testing and analysis · 2026Article
- Stage-specific TRIM10 expression regulates erythroid maturation.EMBO reports · 2025Article
- Medium-Dose Formoterol Attenuated Abdominal Aortic Aneurysm Induced by EPO via β2AR/cAMP/SIRT1 Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis.Nature communications · 2024Article
- Erythropoietin receptor signal is crucial for periodontal ligament stem cell-based tissue reconstruction in periodontal disease.Scientific reports · 2024Article
- The Role of PIK3R1 in Metabolic Function and Insulin Sensitivity.International journal of molecular sciences · 2023Review
- RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia.The Journal of clinical investigation · 2023Article
- The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization.International journal of molecular sciences · 2021Review
- MARCH6 promotes hepatocellular carcinoma development through up-regulation of ATF2.BMC cancer · 2021Article
- Phospho-PTM proteomic discovery of novel EPO- modulated kinases and phosphatases, including PTPN18 as a positive regulator of EPOR/JAK2 Signaling.Cellular signalling · 2020Article
- Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.Science (New York, N.Y.) · 2020Article
- Erythropoietin regulation of red blood cell production: from bench to bedside and back.F1000Research · 2020Review
- P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.Nature communications · 2018Article
- Regulation of Smoothened ubiquitylation and cell surface expression through a Cul4-DDB1-Gβ E3 ubiquitin ligase complex.Journal of cell science · 2018Article
- New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.Haematologica · 2018Article
- Erythropoietin enhances Kupffer cell number and activity in the challenged liver.Scientific reports · 2017Article
- Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis.Diabetes · 2017Article
- Epigenetics in cancer stem cells.Molecular cancer · 2017Review
- Cytokine Receptor Endocytosis: New Kinase Activity-Dependent and -Independent Roles of PI3K.Frontiers in endocrinology · 2017Review
- Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia.Cancer cell · 2016Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Erythropoietin (Epo) binding to the Epo receptor (EpoR) elicits downstream signaling that is essential for red blood cell production. One important negative regulatory mechanism to terminate Epo signaling is Epo-induced EpoR endocytosis and degradation. Defects in this mechanism play a key role in the overproduction of erythrocytes in primary familial and congenital polycythemia (PFCP). Here we have identified a novel mechanism mediating Epo-dependent EpoR internalization. Epo induces Cbl-dependent ubiquitination of the p85 regulatory subunit of PI3K, which binds to phosphotyrosines on EpoR. Ubiquitination allows p85 to interact with the endocytic protein epsin-1, thereby driving EpoR endocytosis. Knockdown of Cbl, expression of its dominant negative forms, or expression of an epsin-1 mutant devoid of ubiquitin-interacting motifs all compromise Epo-induced EpoR internalization. Mutated EpoRs mimicking those from PFCP patients cannot bind p85, co-localize with epsin-1, or internalize on Epo stimulation and exhibit Epo hypersensitivity. Similarly, knockdown of Cbl also causes Epo hypersensitivity in primary erythroid progenitors. Restoring p85 binding to PFCP receptors rescues Epo-induced epsin-1 co-localization and EpoR internalization and normalizes Epo hypersensitivity. Our results uncover a novel Cbl/p85/epsin-1 pathway in EpoR endocytosis and show that defects in this pathway contribute to excessive Epo signaling and erythroid hyperproliferation in PFCP.
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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 OpenQuestion graph.