ArticleNature medicine2011
Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.
Article in Nature medicine, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
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Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
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- Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer.The Journal of clinical investigation · 2026Article
- NMR-Based Fragment Screen of the von Hippel-Lindau Elongin C&B Complex.ACS medicinal chemistry letters · 2025Article
- [Familial erythrocytosis type 2 due to VHL germline mutations: a case report and literature review].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2025Review
- Case Report: Importance of high-throughput genetic investigations in the differential diagnosis of unexplained erythrocytosis.Pathology oncology research : POR · 2025Article
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- STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia.Cell death discovery · 2023Article
- EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
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- Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis.Cancer science · 2022Article
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- Genetic Background of Congenital Erythrocytosis.Genes · 2021Review
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- The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer.Open biology · 2020Review
- Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease.Journal of neuro-oncology · 2020Article
- Thrombotic risk in congenital erythrocytosis due to up-regulated hypoxia sensing is not associated with elevated hematocrit.Haematologica · 2020Article
- Genotype-phenotype relations of the von Hippel-Lindau tumor suppressor inferred from a large-scale analysis of disease mutations and interactors.PLoS computational biology · 2019Article
- Oncogenic Activities Of UBE2S Mediated By VHL/HIF-1α/STAT3 Signal Via The Ubiquitin-Proteasome System In PDAC.OncoTargets and therapy · 2019Article
Corrections and comments
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Authors and funding
19 authors at 6 institutions in 2 countries.
Funding
Abstract
Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.
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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.