Identification and functional characterization of a novel interleukin 17 receptor: a possible mitogenic activation through ras/mitogen-activated protein kinase signaling pathway.
Interleukin-17 receptor (IL-17R) is increasingly emerged as a distinct receptor family functioning in diverse cellular processes including inflammation and cancer. In this study, we uncovered a novel member of IL-17R from mouse tissue that was named mouse IL-17RE (mIL-17R). Mouse IL-17RE cDNA is composed of at least 14 exons and presents at least 6 spliced isoforms (mIL-17RE1-6) with a molecular weight ranging from 34.2 to 70.1 kD. Mouse IL-17RE is expressed in limited tissues such as lung, kidney, stomach, intestine and testis, etc., and is mainly localized in the cytoplasm and on cell membrane. IL-17RE can also be detected in numerous tumor cell lines. Importantly, a mitogenic effect was detected in BaF3 cells stably transfected with the chimeric receptor fused by the ectodomain of erythropoietin receptor (EPOR) with the transmembrane and endomain of IL-17RE in a serum-dependent but EPO-independent manner. Moreover, ERK1/2 phosphorylation was significantly up-regulated as the dose of mIL-17RE increased. Specific RNAi targeting at mIL-17RE dramatically inhibited the activation of ERK1/2, indicating that mIL-17RE could functionally activate RAS/MAPK signaling pathway. Using dominant negative MEK (Dn-MEK) or RAS (Dn-RAS) as a signaling blocker, we were able to show that mIL-17RE probably activated RAS/MAPK signaling at or upstream of RAS. Overall, our results strongly indicate that mIL-17RE may belong to a novel growth-receptor like molecule that has the capability to support cellular mitogenesis through RAS/MAPK pathway.
Li
Tie-Shi
TS
Tsinghua Institute of Genome Research, Department of Biological Sciences and Biotechnology and Institute of Biomedicine, Tsinghua University, Beijing 100084, China.
Li
Xue-Ni
XN
Chang
Zhi-Jie
ZJ
Fu
Xin-Yuan
XY
Liu
Li
L
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D016678:Genome / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008934:Mitogens; D008969:Molecular Sequence Data; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
C491673:Il17ra protein, mouse; D008024:Ligands; D008934:Mitogens; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins