HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsEmmanouil Kyriakakis, Kseniya Maslova, Maria Philippova, Dennis Pfaff, Manjunath B Joshi, Stanislaw A Buechner, Paul Erne, Thérèse J Resink
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 132 Issue 9 Pg. 2275-85 (Sep 2012) ISSN: 1523-1747 [Electronic] United States
PMID22592160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cadherins
  • H-cadherin
  • Quinazolines
  • Lapatinib
  • EGFR protein, human
  • ErbB Receptors
  • rho GTP-Binding Proteins
  • Gefitinib
Topics
  • Cadherins (genetics, physiology)
  • Carcinoma, Squamous Cell (genetics, pathology)
  • Cell Line, Tumor
  • Cell Movement
  • ErbB Receptors (antagonists & inhibitors, physiology)
  • Gefitinib
  • Gene Silencing
  • Humans
  • Lapatinib
  • Membrane Microdomains (metabolism)
  • Quinazolines (pharmacology)
  • Signal Transduction (drug effects, genetics, physiology)
  • Skin Neoplasms (genetics, pathology)
  • rho GTP-Binding Proteins (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: