Document information

3 votes

Tumor-associated EGFR over-expression specifically activates Stat3 and Smad7 resulting in desensitization of TGF-β signaling

Rodney Luwor¹, Lauren Taylor², Bo Wang³, & Hong-Jian Zhu ¹

Correspondence: (Login to view email address)

1. The University of Melbourne, Surgery (RMH)
2. The University of Melbourne
3. University of Melbourne

PDF (975.3 KB)

Document Type:

Manuscript

Date:

Received 23 January 2008 01:47 UTC; Posted 23 January 2008

Subjects:

Cancer, Molecular Cell Biology

Tags:

• This document has not been tagged.

Abstract:

Transforming Growth Factor-β (TGF-β) and Epidermal Growth Factor (EGF) signaling pathways are both independently implicated as key regulators in tumor formation and progression. Here, we demonstrate that activation of the tumor-associated and over-expressed EGFR desensitizes TGF-β signaling and its cytostatic regulation through specific Stat3 activation and Smad7 induction. In normal and tumor human cell lines, reduction of TGF-β-mediated Smad2 phosphorylation, nuclear translocation and Smad3 target gene activation were observed where EGFR is over-expressed, but not in cells which expressed EGFR at normal levels. The EGFR downstream signaling molecules phosphatidyinositol-3 Kinase (PI3K) or mitogen-activated protein kinase/ERK kinase (MEK) are not responsible for the down-regulation of TGF-β signaling since blockade of them by specific pharmacological inhibitors LY294002 and U0126 had little effects on the sensitivity of TGF-β signaling. We identified Stat3 as a signaling molecule activated specifically and persistently by over-expressed EGFR, but not by normal levels. Importantly, Stat3 is responsible for the reduced TGF-β sensitivity, since its knockdown by siRNA restored TGF-β signaling sensitivity. Furthermore, over-expressed EGFR, through Stat3 activates Smad7 promoter activity, increasing its protein levels, which is a negative regulator of TGF-β signaling. Consequently, cells were re-sensitized to TGF-β when Smad7 expression was reduced using siRNA. Therefore we establish a novel EGFR-Stat3-Smad7-TGF-β signaling molecular axis where tumor-associated over-expression of EGFR in epithelial cells results in hyperactivation of Stat3, which activates Smad7 expression, compromising the TGF-β’s cytostatic regulation of epithelium and consequent tumor formation.

Discussion

Votes:

3 votes

(Login to vote)

Comments:

0 comments

(Login to post a comment)

Share:

(Login to share with a colleague)

Additional information

License:

This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Luwor, Rodney, Taylor, Lauren, Wang, Bo, and Zhu , Hong-Jian . Tumor-associated EGFR over-expression specifically activates Stat3 and Smad7 resulting in desensitization of TGF-β signaling. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.1535.1> (2008)

Version info:

Other versions of this document in Nature Precedings

None.

Other versions of this document elsewhere on the web

None known.

Submit a new version link