RGD Reference Report - Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia. - Rat Genome Database

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Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.

Authors: Russell, RC  Sufan, RI  Zhou, B  Heir, P  Bunda, S  Sybingco, SS  Greer, SN  Roche, O  Heathcote, SA  Chow, VW  Boba, LM  Richmond, TD  Hickey, MM  Barber, DL  Cheresh, DA  Simon, MC  Irwin, MS  Kim, WY  Ohh, M 
Citation: Russell RC, etal., Nat Med. 2011 Jun 19;17(7):845-53. doi: 10.1038/nm.2370.
RGD ID: 6483049
Pubmed: PMID:21685897   (View Abstract at PubMed)
PMCID: PMC3221316   (View Article at PubMed Central)
DOI: DOI:10.1038/nm.2370   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
familial erythrocytosis 2  ISOJak2 (Mus musculus)6483049; 6483049 RGD 
familial erythrocytosis 2  IMP 6483049 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Jak2  (Janus kinase 2)

Genes (Mus musculus)
Jak2  (Janus kinase 2)

Genes (Homo sapiens)
JAK2  (Janus kinase 2)


Additional Information