| Affiliation: | 1.The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital,Central South University,Changsha,China;2.Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education,Central South University,Changsha,China;3.Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital,Central South University,Changsha,China;4.Department of Laboratory Medicine, The Second Xiangya Hospital,Central South University,Changsha,China;5.Medical College, University of South China,Hengyang,China;6.Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School,Central South University,Changsha,China;7.Department of Pathology, The Second Xiangya Hospital,Central South University,Changsha,China;8.Department of Ophthalmology, Xiangya Hospital,Central South University,Changsha,China |
| Abstract: | BackgroundAs a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear.MethodsThe interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro. We also investigated the interaction of LRRC4 and ERK1/2 and the role of the D domain in ERK activation in glioma cells.ResultsHere, we showed that LRRC4 and ERK1/2 interact via the D domain and CD domain, respectively. Following EGF stimuli, the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and abrogates ERK1/2 activation and nuclear translocation. In glioblastoma cells, ectopic LRRC4 expression competitively inhibited the interaction of endogenous mitogen-activated protein kinase (MEK) and ERK1/2. Mutation of the D domain decreased the LRRC4-mediated inhibition of MAPK signaling and its anti-proliferation and anti-invasion roles.ConclusionsOur results demonstrated that the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells. These findings identify a new mechanism underlying glioblastoma progression and suggest a novel therapeutic strategy by restoring the activity of LRRC4 to decrease MAPK cascade activation. |
