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

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.

• Authors: Ryan C Russell, Roxana I Sufan, Bing Zhou, Pardeep Heir, Severa Bunda, Stephanie S Sybingco, Samantha N Greer, Olga Roche, Samuel A Heathcote, Vinca W K Chow, Lukasz M Boba, Terri D Richmond, Michele M Hickey, Dwayne L Barber, David A Cheresh, M Celeste Simon, Meredith S Irwin, William Y Kim, Michael Ohh
• Journal: Nature medicine (Nat Med) Vol. 17 Issue 7 Pg. 845-53 (Jun 19 2011) ISSN: 1546-170X [Electronic] United States
• PMID: 21685897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Pyrimidines
• SOCS1 protein, human
• Sulfonamides
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins
• TG101209
• Ubiquitin-Protein Ligases
• Von Hippel-Lindau Tumor Suppressor Protein
• JAK2 protein, human
• Janus Kinase 2
• VHL protein, human

Topics

• Animals
• Disease Models, Animal
• Humans
• Janus Kinase 2 (antagonists & inhibitors, physiology)
• Mice
• Mutation (genetics)
• Polycythemia (etiology, genetics)
• Protein Multimerization (genetics)
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, physiology)
• Ubiquitin-Protein Ligases (genetics, physiology)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, physiology)