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T-Cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma: impact on cell motility

Kyriakakis, Emmanouil and Maslova, Kseniya and Philippova, Maria and Pfaff, Dennis and Joshi, Manjunath B. and Buechner, Stanislaw A. and Erne, Paul and Resink, Thérèse J.. (2012) T-Cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma: impact on cell motility. Journal of investigative dermatology, Vol. 132, H. 9. pp. 2275-2285.

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Official URL: http://edoc.unibas.ch/dok/A6164883

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Abstract

Genetic and epigenetic studies in different cancers, including cutaneous carcinomas, have implicated T-cadherin (T-cad) as a tumor suppressor. Immunohistochemical and in vitro studies have suggested that T-cad loss promotes incipient invasiveness in cutaneous squamous cell carcinoma (SCC). Molecular mechanisms are unknown. This study found that the main consequence of T-cad silencing in SCC is facilitation of ligand-dependent EGFR activation, whereas T-cad overexpression impedes EGFR activation. Gain- and loss-of-function studies in A431 SCC cells demonstrate T-cad-controlled responsiveness to EGF with respect to pharmacological inhibition of EGFR and to diverse signaling and functional events of the EGFR activation cascade (EGFR phosphorylation, internalization, nuclear translocation, cell retraction/de-adhesion, motility, invasion, integrin β1, and Rho small GTPases such as RhoA, Rac1, and Cdc42 activation). Further, T-cad modulates the EGFR pathway activity by influencing membrane compartmentalization of EGFR; T-cad upregulation promotes retention of EGFR in lipid rafts, whereas T-cad silencing releases EGFR from this compartment, rendering EGFR more accessible to ligand stimulation. This study reveals a mechanism for fine-tuning of EGFR activity in SCC, whereby T-cad represents an auxiliary "negative" regulator of the EGFR pathway, which impacts invasion-associated behavioral responses of SCC to EGF. This action of T-cad in SCC may serve as a paradigm explaining other malignancies displaying concomitant T-cad loss and enhanced EGFR activity.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Signal Transduction (Resink/Erne)
UniBasel Contributors:Resink, Thérèse J. and Erne, Paul
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Nature Publishing Group
ISSN:0022-202X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:14
Deposited On:25 Oct 2013 08:33

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