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
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.