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F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation

Dong, S and Zhao, J and Wei, J and Bowser, RK and Khoo, A and Liu, Z and Luketich, JD and Pennathur, A and Ma, H and Zhao, Y (2014) F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation. Molecular Cancer, 13 (1).

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Abstract

Background: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.Methods: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.Results: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.Conclusions: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis. © 2014 Dong et al.; licensee BioMed Central Ltd.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Dong, S
Zhao, Jjiz72@pitt.eduJIZ72
Wei, Jjiw77@pitt.eduJIW77
Bowser, RK
Khoo, A
Liu, Z
Luketich, JDluketich@pitt.eduLUKETICH
Pennathur, Aarjunp@pitt.eduARJUNP0000-0001-7937-7991
Ma, H
Zhao, Yyuz42@pitt.eduYUZ42
Date: 1 April 2014
Date Type: Publication
Journal or Publication Title: Molecular Cancer
Volume: 13
Number: 1
DOI or Unique Handle: 10.1186/1476-4598-13-76
Schools and Programs: School of Medicine > Medicine
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 02 Dec 2016 20:38
Last Modified: 03 Feb 2020 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/29582

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