title: Cross-talk between EGFR and T-cadherin: EGFR activation promotes T-cadherin localization to intercellular contacts.
abstract: Reciprocal cross-talk between receptor tyrosine kinases (RTKs) and classical cadherins (e.g. EGFR/E-cadherin, VEGFR/VE-cadherin) has gained appreciation as a combinatorial molecular mechanism enabling diversification of the signalling environment and according differential cellular responses. Atypical glycosylphosphatidylinositol (GPI)-anchored T-cadherin (T-cad) was recently demonstrated to function as a negative auxiliary regulator of EGFR pathway activation in A431 squamous cell carcinoma (SCC) cells. Here we investigate the reciprocal impact of EGFR activation on T-cad. In resting A431 T-cad was distributed globally over the cell body. Following EGF stimulation T-cad was redistributed to the sites of cell-cell contact where it colocalized with phosphorylated EGFR(Tyr1068). T-cad redistribution was not affected by endomembrane protein trafficking inhibitor brefeldin A or de novo protein synthesis inhibitor cycloheximide, supporting mobilization of plasma membrane associated T-cad. EGF-induced relocalization of T-cad to cell-cell contacts could be abrogated by specific inhibitors of EGFR tyrosine kinase activity (gefitinib or lapatinib), lipid raft integrity (filipin), actin microfilament polymerization (cytochalasin D or cytochalasin B), p38MAPK (SB203580) or Rac1 (compound4). Erk1/2 inhibitor PD98059 increased phospho-EGFR(tyr1068) levels and not only amplified effects of EGF but also per se promoted some relocalization of T-cad to cell-cell contacts. Rac1 activation by EGF was inhibited by gefitinib, lapatinib or SB203580 but amplified by PD98059. Taken together our data suggest that T-cad translocation to cell-cell contacts is sensitive to the activity status of EGFR, requires lipid raft domain integrity and actin filament polymerization, and crucial intracellular signalling mediators include Rac1 and p38MAPK. The study has revealed a novel aspect of reciprocal cross-talk between EGFR and T-cad.
authors: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland.
authors: Emmanouil
authors: E
authors: Kyriakakis
authors: Kseniya
authors: K
authors: Maslova
authors: Audrey
authors: A
authors: Frachet
authors: Nicola
authors: N
authors: Ferri
authors: Alessandro
authors: A
authors: Contini
authors: Dennis
authors: D
authors: Pfaff
authors: Paul
authors: P
authors: Erne
authors: Therese J
authors: TJ
authors: Resink
authors: Maria
authors: M
authors: Philippova
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D015820:Cadherins; C099972:H-cadherin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D000077156:Gefitinib