Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity.
Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity.
复制标题
DOI：
10.1042/bj20110351
复制
发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Reuther GW
中科院分区：
文献类型：
--
作者：
Lambert QT;Pradhan A;Roll JD;Reuther GW
Cytokines and their receptors regulate hematopoiesis by controlling cellular growth, survival, and differentiation. Thus, it is not surprising that mutations of cytokine receptors contribute to the formation of hematopoietic disorders including cancer. We recently identified transforming properties of the ligand-binding component of the receptor for interleukin-27 (IL27R). While wildtype IL27R exhibits transforming properties in hematopoietic cells, in this 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 hematopoietic cells. Moreover, the rate of transformation induced by these mutants was significantly greater than that induced by wildtype IL27R. Expression of these IL27R mutants also induced enhanced activation of JAK/STAT signaling compared to wildtype. 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 hematopoietic oncogenes such as BCR-ABL and JAK2-V617F. Since IL27R is expressed on hematopoietic stem cells, lymphoid cells, and myeloid cells, including AML blast cells, mutation of this receptor has the potential to contribute to a variety of hematopoietic neoplasms.
