{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:26:04Z","timestamp":1791271564705,"version":"4.1.0"},"reference-count":67,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:p>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 3) have remained unclear. In the present study, using recombinant purified JAK2JH1-JH2 proteins, we demonstrate that, when activated, wild-type and myeloproliferative neoplasm-associated mutants of JAK2 exhibit comparable enzymatic activity and inhibition by SOCS3 in in\u00a0vitro kinase assays. SAXS (small-angle X-ray scattering) showed that JAK2JH1-JH2 exists in an elongated configuration in solution with no evidence for interaction between JH1 and JH2 domains in cis. Collectively, these data are consistent with a model in which JAK2's pseudokinase domain does not influence the activity of JAK2 once it has been activated. Our data indicate that, in the absence of the N-terminal FERM domain and thus cytokine receptor association, the wild-type and pathological mutants of JAK2 are enzymatically equivalent and equally susceptible to inhibition by SOCS3.<\/jats:p>","DOI":"10.1042\/bj20131516","type":"journal-article","created":{"date-parts":[[2013,12,20]],"date-time":"2013-12-20T09:37:45Z","timestamp":1387532265000},"page":"395-405","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses"],"prefix":"10.1042","volume":"458","author":[{"given":"Leila\u00a0N.","family":"Varghese","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ungureanu","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Tampere and Tampere University Hospital, Tampere 33014, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas\u00a0P. D.","family":"Liau","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel\u00a0N.","family":"Young","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Laktyushin","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Hammaren","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Tampere and Tampere University Hospital, Tampere 33014, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle\u00a0S.","family":"Lucet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicos\u00a0A.","family":"Nicola","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Silvennoinen","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Tampere and Tampere University Hospital, Tampere 33014, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey\u00a0J.","family":"Babon","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James\u00a0M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2014,2,14]]},"reference":[{"key":"2021112216011020500_B1","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(05)71142-9","article-title":"Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders","volume":"365","author":"Baxter","year":"2005","journal-title":"Lancet"},{"key":"2021112216011020500_B2","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1042\/BST20130084","article-title":"Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers","volume":"41","author":"Constantinescu","year":"2013","journal-title":"Biochem. 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