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Title: The myeloproliferative disorder-associated JAK2V617F mutant escapes negative regulation by SOCS-3
Author: Hookham, Michelle Bernadette
ISNI:       0000 0001 3581 3122
Awarding Body: Queen's University of Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in more than 90% of patients with polycythaemia vera (PV) and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). Suppressor of cytokine signalling 3 (SOCS-3) is known to be a strong negative regulator of erythropoietin (EPO) signalling through interaction with both the EPO receptor (EPOR) and JAK2. We report that JAK2V617F phosphorylation can be actually potentiated in the presence of SOCS-3. Instead of acting as a suppressor, SOCS-3 enhanced the proliferation of cells expressing both JAK2V617F and EPOR. Additionally, turnover of SOCS-3 was inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation and stabilization ofSOCS-3 protein. We also observed constitutive tyrosine phosphorylation of SOCS-3 in granulocytes and peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2V617F mutation. We also discovered that other recently identified MPD-associated mutations were also able to hyper-phosphorylate SOCS-3. These findings suggest that JAK2V617F and the other MPD-associated JAK2 mutations have overcome normal regulation by aberrantly phosphorylating SOCS-3, rendering it unable to inhibit these mutant kinases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available