Journal article
Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses
LN Varghese, D Ungureanu, NPD Liau, SN Young, A Laktyushin, H Hammaren, IS Lucet, NA Nicola, O Silvennoinen, JJ Babon, JM Murphy
Biochemical Journal | Published : 2014
DOI: 10.1042/BJ20131516
Abstract
JAK2 (Janus kinase 2) initiates the intracellular signalling cascade downstream of cell surface receptor activation by cognate haemopoietic cytokines, including erythropoietin and thrombopoietin. The pseudokinase domain (JH2) of JAK2 negatively regulates the catalytic activity of the adjacent tyrosine kinase domain (JH1) and mutations within the pseudokinase domain underlie human myeloproliferative neoplasms, including polycythaemia vera and essential thrombocytosis. To date, the mechanism of JH2-mediated inhibition of JH1 kinase activation as well as the susceptibility of pathological mutant JAK2 to inhibition by the physiological negative regulator SOCS3 (suppressor of cytokine signalling ..
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Awarded by National Cancer Institute
Funding Acknowledgements
This work was supported by the NHMRC (National Health and Medical Research Council) [grant numbers 1011 804 and 1016647], the National Institutes of Health [grant number CA-22556]; Leukaemia Foundation and Australian Stem Cell Centre scholarships (to L.N.V.); an NHMRC fellowship (to N.A.N.), ARC (Australian Research Council) fellowships [grants FT110100169 and FT100100100 (to J.J.B. and J M.M)]; the Medical Research Council of Academy of Finland, the Sigrid Juselius Foundation, the Medical Research Fund of Tampere University Hospital, the Finnish Cancer Foundation and the Tampere Tuberculosis Foundation (to U.S.). There was additional support from the Victorian State Government Operational Infrastructure Support and NHMRC IRIISS (Victorian State Government Operational Infrastructure Support) [grant number 361646].