title: The D Domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells.
abstract: As 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.
  
  
  
  The 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.
  
  
  
  Here, 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.
  
  
  
  Our 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.
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.|Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Zeyou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Guo
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Medical College, University of South China, Hengyang, Hunan, 421001, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Peiyao
authors.initials: P
authors.lastname: Li
authors.affiliation: Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China.
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.|Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: She
authors.affiliation: Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China.|Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. lgy@csu.edu.cn.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China. lgy@csu.edu.cn.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. lgy@csu.edu.cn.
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.affiliation: The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. wuminghua554@aliyun.com.|Cancer Research Institute, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, Hunan, 410008, China. wuminghua554@aliyun.com.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China. wuminghua554@aliyun.com.
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
mesh_terms: D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000494:pharmacology; D000072417:Protein Domains / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: C503331:LRRC4 protein, human; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors
keywords: CD domain; D domain; ERK1/2; Leucine-rich repeat; MAPK