Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X.
We found that in addition to influencing catalytic activities the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition.
The data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis.
WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFbeta1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFbeta1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
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