The discovery of the highly prevalent activating JAK (Janus kinase) 2 V617F mutation in myeloproliferative neoplasms, and of other pseudokinase domain-activating mutations in JAK2, JAK1 and JAK3 in blood cancers, prompted great interest in understanding how pseudokinase domains regulate kinase domains in JAKs. Recent functional and mutagenesis studies identified residues required for the V617F mutation to induce activation. Several X-ray crystal structures of either kinase or pseudokinase domains including the V617F mutant of JAK2 pseudokinase domains are now available, and a picture has emerged whereby the V617F mutation induces a defined conformational change around helix C of JH (JAK homology) 2. Effects of mutations on JAK2 can be extrapolated to JAK1 and TYK2 (tyrosine kinase 2), whereas JAK3 appears to be different. More structural information of the full-length JAK coupled to cytokine receptors might be required in order to define the structural basis of JH1 activation by JH2 mutants and eventually obtain mutant-specific inhibitors.
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Conference Article|
July 18 2013
Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers
Stefan N. Constantinescu;
Stefan N. Constantinescu
1
1Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium
1To whom correspondence should be addressed (emailstefan.constantinescu@bru.licr.org).
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Emilie Leroy;
Emilie Leroy
1Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium
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Vitalina Gryshkova;
Vitalina Gryshkova
1Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium
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Christian Pecquet;
Christian Pecquet
1Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium
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Alexandra Dusa
Alexandra Dusa
1Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium
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Publisher: Portland Press Ltd
Received:
May 20 2013
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem Soc Trans (2013) 41 (4): 1048–1054.
Article history
Received:
May 20 2013
Citation
Stefan N. Constantinescu, Emilie Leroy, Vitalina Gryshkova, Christian Pecquet, Alexandra Dusa; Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers. Biochem Soc Trans 1 August 2013; 41 (4): 1048–1054. doi: https://doi.org/10.1042/BST20130084
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