title: Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity.
abstract: Cytokines and their receptors regulate haemopoiesis by controlling cellular growth, survival and differentiation. Thus it is not surprising that mutations of cytokine receptors contribute to the formation of haemopoietic disorders, including cancer. We recently identified transforming properties of IL27R, the ligand-binding component of the receptor for interleukin-27. Although wild-type IL27R exhibits transforming properties in haemopoietic cells, in the present study we set out to determine if the transforming activity of IL27R could be enhanced by mutation. We identified three mutations of IL27R that enhance its transforming activity. One of these mutations is a phenylalanine to cysteine mutation at residue 523 (F523C) in the transmembrane domain of the receptor. The two other mutations identified involve deletions of amino acids in the cytoplasmic juxtamembrane region of the receptor. Expression of each of these mutant IL27R proteins led to rapid cytokine-independent transformation in haemopoietic cells. Moreover, the rate of transformation induced by these mutants was significantly greater than that induced by wild-type IL27R. Expression of these IL27R mutants also induced enhanced activation of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling compared with wild-type. An activating deletion mutation of IL27R enhanced homodimerization of the receptor by a mechanism that may involve disulfide bonding. These transforming IL27R mutants displayed equal or greater transforming activity than bona fide haemopoietic oncogenes such as BCR-ABL (breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue) and JAK2-V617F. Since IL27R is expressed on haemopoietic stem cells, lymphoid cells and myeloid cells, including acute myeloid leukaemia blast cells, mutation of this receptor has the potential to contribute to a variety of haemopoietic neoplasms.
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Que T
authors.initials: QT
authors.lastname: Lambert
authors.forename: Anuradha
authors.initials: A
authors.lastname: Pradhan
authors.forename: J Devon
authors.initials: JD
authors.lastname: Roll
authors.forename: Gary W
authors.initials: GW
authors.lastname: Reuther
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019281:Dimerization; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology*; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C112441:IL27RA protein, human; C484747:Il27ra protein, mouse; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; D016044:Fusion Proteins, bcr-abl; C507904:JAK1 protein, human; D053613:Janus Kinase 1