Abstract
Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Movement*
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Down-Regulation / genetics
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism*
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Gene Expression Regulation, Neoplastic / genetics
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Glioma / genetics
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Glioma / metabolism*
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Glioma / pathology
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Nedd4 Ubiquitin Protein Ligases
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Neoplasm Invasiveness
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination*
Substances
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Endosomal Sorting Complexes Required for Transport
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Guanine Nucleotide Exchange Factors
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Neoplasm Proteins
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Nerve Tissue Proteins
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RAPGEF2 protein, human
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Nedd4 Ubiquitin Protein Ligases
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Nedd4 protein, human
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Ubiquitin-Protein Ligases
Grants and funding
The project was supported by National Natural Science Foundation of China (No. 81072072; No. 81272777); Natural Science Foundation of Jiangsu Province (No. BK2011195); The Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); and Program for New Century Excellent Talents in University (NCET-10-0181). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.