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Deprecated: Implicit conversion from float 253.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Commun+Signal 2018 ; 16 (ä): ä Nephropedia Template TP
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Ras enhances TGF-? signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1 #MMPMID29534718
Liu S; Iaria J; Simpson RJ; Zhu HJ
Cell Commun Signal 2018[]; 16 (ä): ä PMID29534718show ga
Background: Transformation by oncogene Ras overcomes TGF-? 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-? 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-? 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-? signaling. Ras interacts and colocalizes with the TGF-? type II receptor?s (T?RII) 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 T?RII, 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-? signaling and its mediated migration and invasion. Conclusion: Ras positively cooperates with TGF-? signaling by reducing the cellular protein levels of T?RII negative regualtor SPSB1. Electronic supplementary material: The online version of this article (10.1186/s12964-018-0223-4) contains supplementary material, which is available to authorized users.