title: JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor.
abstract: The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels B-1200, Belgium.
authors.forename: Judith
authors.initials: J
authors.lastname: Staerk
authors.forename: Anders
authors.initials: A
authors.lastname: Kallin
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D053613:Janus Kinase 1; D008024:Ligands; D009154:Mutation; D011087:Polycythemia Vera / Q000201:enzymology* / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D008024:Ligands; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human