Abstract
Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 and kinase MEKK5 both play an essential role in lung cancer migration. A report predicts that MEKK5 may be ubiquitinated by NEDD4; however, interaction of MEKK5 with NEDD4 and ubiquitination of MEKK5 by NEDD4 have not been characterized. In this report, we show that NEDD4 interacts with MEKK5 through a conserved WW3 domain by the co-immunoprecipitation and the GST-pulldown assays. The ubiquitination assay indicates that MEKK5 is not a ubiquitination substrate of NEDD4, but negatively regulates NEDD4-mediated ubiquitination. Furthermore, overexpression of MEKK5 significantly reduced the NEDD4-promoted lung cancer cell migration. Taken together, our studies have defined an inhibitory role of MEKK5 in regulation of NEDD4-mediated ubiquitination.
Highlights
Neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4), a well-known HECT domain-containing E3 ubiquitin ligase, was originally identified in the early embryonic mouse central nervous system and plays important roles in numerous cellular processes by interacting with many proteins [1,2,3,4]
It is known that NEDD4 family E3 ubiquitin ligases have a central region containing
Sequence analysis showed that MEKK5 has a PPFY motif, suggesting that NEDD4 family E3 ubiquitin ligases may directly interact with MEKK5
Summary
Neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4), a well-known HECT domain-containing E3 ubiquitin ligase, was originally identified in the early embryonic mouse central nervous system and plays important roles in numerous cellular processes by interacting with many proteins [1,2,3,4]. Subsequent studies broadened the functional spectrum of NEDD4 and found that NEDD4 is involved in regulating receptor endocytic trafficking, viral budding, and the neural development process [7,8,9,10,11]. Our recent studies observed that NEDD4 directly interacts with the key autophagosomal protein LC3B via its LC3-interactive region (LIR) and ubiquitinates the autophagic receptor. How the E3 ubiquitin ligase activity of NEDD4 is regulated in cells remains elusive
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