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The D Domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells
Authors:Zeyou?Wang,Rong?Wang,Gang?Xu,Peiyao?Li,Yingnan?Sun,Xiaoling?She,Qiong?Chen,Zhibin?Yu,Changhong?Liu,Jing?Xiong,Guiyuan?Li  author-information"  >  author-information__contact u-icon-before"  >  mailto:lgy@csu.edu.cn"   title="  lgy@csu.edu.cn"   itemprop="  email"   data-track="  click"   data-track-action="  Email author"   data-track-label="  "  >Email author,Minghua?Wu  author-information"  >  author-information__contact u-icon-before"  >  mailto:wuminghua@aliyun.com"   title="  wuminghua@aliyun.com"   itemprop="  email"   data-track="  click"   data-track-action="  Email author"   data-track-label="  "  >Email author
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:

Background

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.

Methods

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.

Results

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.

Conclusions

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.
Keywords:
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