T-cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma

Impact on cell motility

Emmanouil Kyriakakis, Kseniya Maslova, Maria Philippova, Dennis Pfaff, Manjunath B. Joshi, Stanislaw A. Buechner, Paul Erne, Thérèse J. Resink

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2275-2285
Number of pages11
JournalJournal of Investigative Dermatology
Volume132
Issue number9
DOIs
Publication statusPublished - 09-2012

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Cell Movement
Squamous Cell Carcinoma
Skin
Chemical activation
Epidermal Growth Factor
Ligands
rho GTP-Binding Proteins
Phosphorylation
Monomeric GTP-Binding Proteins
Skin Neoplasms
Epigenomics
Integrins
H-cadherin
Epithelial Cells
Tumors
Neoplasms
Up-Regulation
Adhesion
Tuning
Pharmacology

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Kyriakakis, Emmanouil ; Maslova, Kseniya ; Philippova, Maria ; Pfaff, Dennis ; Joshi, Manjunath B. ; Buechner, Stanislaw A. ; Erne, Paul ; Resink, Thérèse J. / T-cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma : Impact on cell motility. In: Journal of Investigative Dermatology. 2012 ; Vol. 132, No. 9. pp. 2275-2285.
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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; Maslova, Kseniya; Philippova, Maria; Pfaff, Dennis; Joshi, Manjunath B.; Buechner, Stanislaw A.; Erne, Paul; Resink, Thérèse J.

In: Journal of Investigative Dermatology, Vol. 132, No. 9, 09.2012, p. 2275-2285.

Research output: Contribution to journalArticle

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AU - Kyriakakis, Emmanouil

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