Article (Scientific journals)
SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling.
Haan, Serge; Wuller, S.; Kaczor, Jakub et al.
2009In Oncogene, 28 (34), p. 3069-80
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Keywords :
Cell Line, Tumor; Cytokines/physiology; Down-Regulation; Humans; Janus Kinase 2/physiology; Mutation; Proteasome Endopeptidase Complex/physiology; Protein Transport; RNA, Messenger/analysis; STAT5 Transcription Factor/metabolism; Signal Transduction/physiology; Suppressor of Cytokine Signaling Proteins/genetics/physiology
Abstract :
[en] Recently, mutations in the gene of Janus kinase 2 (Jak2) were discovered in patients suffering from chronic myeloproliferative disorders (MPD) and leukemia. As suppressors of cytokine signaling (SOCS) proteins are potent feedback inhibitors of Jak-mediated signaling, we investigated their role in signal transduction through constitutively active Jak2 mutants. We selected two mutants, Jak2-V617F and Jak2-K539L, found in patients with MPDs and Jak2-T875N identified in acute megakaryoblastic leukemia. We found SOCS family members to be induced through Jak2-V617F in human leukemia cell lines expressing the mutant allele and in stable HEK transfectants inducibly expressing constitutively active Jak2 mutants. SOCS proteins were recruited to the membrane and bound to the constitutively active Jaks. In contrast to wild-type Jak2, the mutant proteins were constitutively ubiquitinated and degraded through the proteasome. Taken together, we show a SOCS-mediated downregulation of the constitutively active, disease-associated mutant Jak2 proteins. Furthermore, a threshold level of mutant Jak expression has to be overcome to allow full cytokine-independent constitutive activation of signaling proteins, which may explain progression to homozygocity in MPDs as well as gene amplification in severe phenotypes and leukemia.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Haan, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Wuller, S.
Kaczor, Jakub
Rolvering, Catherine ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Nocker, T.
Behrmann, Iris ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Haan, Claude ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Language :
English
Title :
SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling.
Publication date :
2009
Journal title :
Oncogene
ISSN :
1476-5594
Publisher :
Nature Publishing Group, United Kingdom
Volume :
28
Issue :
34
Pages :
3069-80
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
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