Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation

Citation
S. Pece et Js. Gutkind, Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation, J BIOL CHEM, 275(52), 2000, pp. 41227-41233
Citations number
26
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
275
Issue
52
Year of publication
2000
Pages
41227 - 41233
Database
ISI
SICI code
0021-9258(200012)275:52<41227:SFETTM>2.0.ZU;2-V
Abstract
E-cadherins are well characterized cell surface molecules expressed in epit helial cells, which play a major role in cell adhesion through the establis hment of calcium-dependent hemophilic interactions at sites of cell-cell co ntacts. They are also integral components of morphogenetic programs control ling the maintenance of the structural and functional integrity of epitheli a, Accumulated evidence indicates that the E-cadherin-mediated cell adhesio n system is highly regulated from inside the cells by a number of intracell ular signaling pathways. Recently available information suggests that E-cad herins may also play a role in the transduction of signals from the outside of the cell to the cytoplasm. However, the nature of the biochemical route s regulated by E-cadherins is still largely unknown. In this study, we set out to explore the possibility that E-cadherins may regulate the activity o f MAPK, a key signaling pathway involved in cell fate decisions, upon the f ormation of cell-cell contacts among neighboring cells. By using an immorta lized non-tumorigenic keratinocyte cell line, HaCat, as a model system, we provide evidence that the assembly of calcium-dependent adherens junctions leads to a rapid and remarkable increase in the state of activation of MAPK and that this event is mediated by E-cadherins. Furthermore, we found that E-cadherins stimulate the MAPK pathway through the ligand-independent acti vation of epidermal growth factor receptors and the consequent activation o f a biochemical route leading to the stimulation of MAPKs. These findings s uggest that E-cadherins can initiate outside-in signal transducing pathways through the engagement of tyrosine kinase receptors for epidermal growth f actor, thus providing a novel molecular mechanism whereby these cell adhesi on molecules may ultimately control the fate of normal and transformed epit helial cells.