Ras enhances TGF-beta signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1
Web of Science
AuthorLiu, S; Iaria, J; Simpson, RJ; Zhu, H-J
Source TitleCell Communication and Signaling
PublisherBIOMED CENTRAL LTD
Surgery (Austin & Northern Health)
Document TypeJournal Article
CitationsLiu, S., Iaria, J., Simpson, R. J. & Zhu, H. -J. (2018). Ras enhances TGF-beta signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1. CELL COMMUNICATION AND SIGNALING, 16 (1), https://doi.org/10.1186/s12964-018-0223-4.
Access StatusOpen Access
BACKGROUND: Transformation by oncogene Ras overcomes TGF-β mediated growth inhibition in epithelial cells. However, it cooperates with each other to mediate epithelial to mesenchymal transition (EMT). The mechanism of how these two pathways interact with each other is controversial. METHODS: Molecular techniques were used to engineer expression plasmids for Ras, SPRY, TGF-β receptors, type I and II and ubiquitin. Immunoprecipitation and western blots were employed to determine protein-protein interactions, preotein levels, protein phosphorylation while immunofluorecesent staining for molecular co-localization. TGF-β signalling activities is also determined by its luciferase reporter assay. Trans-well assays were used to measure cell migration and invasion. RESULTS: Ras interacts with the SPSB1's SPRY domain to enhance TGF-β signaling. Ras interacts and colocalizes with the TGF-β type II receptor's (TβRII) negative regulator SPSB1 on the cell membrane, consequently promoting SPSB1 protein degradation via enhanced mono- and di-ubiquitination. Reduced SPSB1 levels result in the stablization of TβRII, in turn the increase of receptor levels significantly enhance Smad2/3 phosphorylation and signaling. Importantly, forced expression of SPSB1 in Ras transformed cells suppresses TGF-β signaling and its mediated migration and invasion. CONCLUSION: Ras positively cooperates with TGF-β signaling by reducing the cellular protein levels of TβRII negative regualtor SPSB1.
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