The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3.
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.
Hookham
Michelle B
MB
Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queen's University, 97 Lisburn Road, Belfast, Northern Ireland, UK.
Elliott
Joanne
J
Suessmuth
Yvonne
Y
Staerk
Judith
J
Ward
Alister C
AC
Vainchenker
William
W
Percy
Melanie J
MJ
McMullin
Mary Frances
MF
Constantinescu
Stefan N
SN
Johnston
James A
JA
D000818:Animals; D004921:Erythropoietin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology*; D010649:Phenylalanine / Q000737:chemistry; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014633:Valine / Q000737:chemistry
C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004921:Erythropoietin; D010649:Phenylalanine; D053614:Janus Kinase 2; D014633:Valine