title: T-Cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma: impact on cell motility.
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.
authors.affiliation: Laboratory for Signal Transduction, Department of Biomedicine, Basel University Hospital, Basel, Switzerland.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kyriakakis
authors.forename: Kseniya
authors.initials: K
authors.lastname: Maslova
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
authors.forename: Dennis
authors.initials: D
authors.lastname: Pfaff
authors.forename: Manjunath B
authors.initials: MB
authors.lastname: Joshi
authors.forename: Stanislaw A
authors.initials: SA
authors.lastname: Buechner
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.forename: Thérèse J
authors.initials: TJ
authors.lastname: Resink
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D020868:Gene Silencing; D006801:Humans; D000077341:Lapatinib; D021962:Membrane Microdomains / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; C099972:H-cadherin; D011799:Quinazolines; D000077341:Lapatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D020741:rho GTP-Binding Proteins; D000077156:Gefitinib