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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    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.",
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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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