Skip Navigation



Carcinogenesis Advance Access published online on January 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn003
This Article
Right arrow Advance Access manuscript (PDF)
Right arrow All Versions of this Article:
29/3/552    most recent
bgn003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Zhang, K.
Right arrow Articles by Wang, M.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, K.
Right arrow Articles by Wang, M.-H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Activation of RON Differentially Regulates Claudin Expression and Localization: Role of Claudin-1 in RON-Mediated Epithelial Cell Motility

Kun Zhang1,2, Hang-Ping Yao1 and Ming-Hai Wang1,2,*

1 Laboratory of Cancer Biology and Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China 310003
2 Cancer Biology Center and Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA

* To whom correspondence should be addressed: Email: minghai.wang{at}ttuhsc.edu.

Claudins are integral membrane proteins essential in tight junction formation and function. Altered expression of claudins has been implicated in epithelial malignant transformation. We report here that activation of RON differentially regulates tight junction function and claudin expression. In Martin-Darby canine kidney (MDCK) cells, MSP-induced RON activation or expression of constitutively active variant RON160 significantly disrupted cellular tight junctions and reduced transepithelial electric resistance. These changes were featured by diminished claudin-1 expression and redistribution of claudin-3 and 4 into cytoplasmic compartments. The inhibition of claudin-1 was also seen in breast cancer T-47D cells. By analyzing the signaling events, we found that activation of the Erk1/2 pathway is required for RON-mediated inhibition of claudin-1 expression and redistribution of claudin-3 and 4. Results from luciferase reporter assays showed that inhibition is acted at the transcriptional levels because RON activation decreases claudin-1 promoter activities and increases transcriptional repressor Snail-1 expression. Functional analysis further revealed that reduced claudin-1 expression is linked to increased motilities of MDCK and T-47D cells as evident in cell migration and wound healing assays. Forced expression of claudin-1 prevented RON-mediated cell migration and restored cell morphologies to their original epithelial appearance. In conclusion, RON activation differentially regulates claudin expression in epithelial cells. Inhibition of claudin-1 expression may represent a novel mechanism that contributes to RON-mediated invasive activities leading to increased tumor malignancy.

Key Words: receptor tyrosine kinase • tight junction • claudins • cell migration • breast cancer

Received September 3, 2007; revised December 13, 2007; accepted December 25, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.