title: Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels B1200, Belgium. stefan.constantinescu@bru.licr.org
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Emilie
authors.initials: E
authors.lastname: Leroy
authors.forename: Vitalina
authors.initials: V
authors.lastname: Gryshkova
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dusa
mesh_terms: D019337:Hematologic Neoplasms / Q000201:enzymology*; D006801:Humans; D053612:Janus Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000201:enzymology*
chemical_list: D053612:Janus Kinases