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The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3.
Hookham, Michelle B; Elliott, Joanne; Suessmuth, Yvonne; Staerk, Judith; Ward, Alister C; Vainchenker, William; Percy, Melanie J; McMullin, Mary Frances; Constantinescu, Stefan N; Johnston, James A.
Afiliación
  • Hookham MB; Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queen's University, 97 Lisburn Road, Belfast, Northern Ireland, UK.
Blood ; 109(11): 4924-9, 2007 Jun 01.
Article en En | MEDLINE | ID: mdl-17317861
ABSTRACT
The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.
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Banco de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / Proteínas Supresoras de la Señalización de Citocinas / Janus Quinasa 2 / Mutación / Trastornos Mieloproliferativos Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Blood Año: 2007 Tipo del documento: Article País de afiliación: Reino Unido
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Banco de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / Proteínas Supresoras de la Señalización de Citocinas / Janus Quinasa 2 / Mutación / Trastornos Mieloproliferativos Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Blood Año: 2007 Tipo del documento: Article País de afiliación: Reino Unido