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.