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, Vainchenker, William, Percy, Melanie J., McMullin, Mary Frances, Constantinescu, Stefan N. and Johnston, James A. 2007, The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3, Blood, vol. 109, no. 11, pp. 4924-4929.


Title The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3
Author(s) Hookham, Michelle B.
Elliott, Joanne
Suessmuth, Yvonne
Staerk, Judith
Ward, Alister
Vainchenker, William
Percy, Melanie J.
McMullin, Mary Frances
Constantinescu, Stefan N.
Johnston, James A.
Journal name Blood
Volume number 109
Issue number 11
Start page 4924
End page 4929
Publisher American Society of Hematology
Place of publication Washington, D.C., Wash.
Publication date 2007-06-01
ISSN 0006-4971
1528-0020
Summary 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.
Language eng
Field of Research 110202 Haematology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2007, American Society of Hematology
Persistent URL http://hdl.handle.net/10536/DRO/DU:30007518

Document type: Journal Article
Collection: School of Medicine
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