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.
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Research Article|
July 27 2011
Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity
Que T. Lambert;
Que T. Lambert
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A.
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Anuradha Pradhan;
Anuradha Pradhan
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A.
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J. Devon Roll;
J. Devon Roll
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A.
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Gary W. Reuther
Gary W. Reuther
1
1Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A.
1To whom correspondence should be addressed (email gary.reuther@moffitt.org).
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Publisher: Portland Press Ltd
Received:
February 24 2011
Revision Received:
May 17 2011
Accepted:
June 01 2011
Accepted Manuscript online:
June 01 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (1): 155–164.
Article history
Received:
February 24 2011
Revision Received:
May 17 2011
Accepted:
June 01 2011
Accepted Manuscript online:
June 01 2011
Citation
Que T. Lambert, Anuradha Pradhan, J. Devon Roll, Gary W. Reuther; Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity. Biochem J 15 August 2011; 438 (1): 155–164. doi: https://doi.org/10.1042/BJ20110351
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