title: The Stat3-activating Tyk2 V678F mutant does not up-regulate signaling through the type I interferon receptor but confers ligand hypersensitivity to a homodimeric receptor.
abstract: Tyk2 is a Jak family member involved in cytokine signaling through heterodimeric-type receptors. Here, we analyzed the impact of the Val(678)-to-Phe substitution on Tyk2 functioning. This mutation is homologous to the Jak2 Val(617)-to-Phe mutation, implicated in myeloproliferative disorders. We studied ligand-independent and ligand-dependent Jak/Stat signaling in cells expressing Tyk2 V678F. Moreover, the effect of Tyk2 V678F was monitored in the context of the native heterodimeric interferon alpha receptor and in the context of a homodimeric receptor chimera, EpoR/R1, containing the ectodomain of the erythropoietin receptor. We show that Tyk2 V678F has increased catalytic potential in vivo and in vitro and more so when it is anchored to the homodimeric receptor. Tyk2 V678F leads to constitutive Stat3 phosphorylation but has no notable effect on the canonical interferon alpha-induced signaling. However, if anchored to the homodimeric EpoR/R1, the mutant confers to the cell increased sensitivity to erythropoietin. Thus, despite the catalytic gain of function of Tyk2 V678F, the effect on ligand-induced signaling is manifest only when two mutant enzymes are juxtaposed via the homodimeric receptor.
authors.affiliation: Cytokine Signaling Unit, CNRS URA 1961, Institut Pasteur, Paris 75724, France.
authors.forename: Milica
authors.initials: M
authors.lastname: Gakovic
authors.forename: Josiane
authors.initials: J
authors.lastname: Ragimbeau
authors.forename: Véronique
authors.initials: V
authors.lastname: Francois
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D019281:Dimerization; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D020125:Mutation, Missense; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: C508033:IFNAR2 protein, human; D008024:Ligands; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004921:Erythropoietin; D053633:Receptor, Interferon alpha-beta; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human