Activation of the Protein Kinase Akt/PKB by the Formation of E-cadherin-mediated Cell-Cell Junctions

Abstract

E-cadherins are surface adhesion molecules localized at the level of adherens junctions, which play a major role in cell adhesiveness by mediating calcium-dependent homophylic interactions at sites of cell-cell contacts. Recently, E-cadherins have been also implicated in a number of biological processes, including cell growth and differentiation, cell recognition, and sorting during developmental morphogenesis, as well as in aggregationdependent cell survival. As phosphatidylinositol (PI) 3-kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli, these observations prompted us to explore whether E-cadherins could affect intracellular molecules regulating the activity of the PI 3-kinase/Akt signaling cascade. Using Madin-Darby canine kidney cells as a model system, we show here that engagement of E-cadherins in homophylic calcium-dependent cell-cell interactions results in a rapid PI 3-kinase-dependent activation of Akt and the subsequent translocation of Akt to the nucleus. Moreover, we demonstrate that the activation of PI 3-kinase in response to cell-cell contact formation involves the phosphorylation of PI 3-kinase in tyrosine residues, and the concomitant recruitment of PI 3-kinase to E-cadherin-containing protein complexes. These findings indicate that E-cadherins can initiate outside-in signal transducing pathways that regulate the activity of PI 3-kinase and Akt, thus providing a novel molecular mechanism whereby the interaction among neighboring cells and their adhesion status may ultimately control the fate of epithelial cells.The maintenance of structural and functional integrity of epithelia requires highly dynamic cell-to-cell and cell-to-matrix interactions, which are mediated by adhesion mechanisms involving different types of cell-surface receptors. Among them, cadherins and integrins play a major role, as they are able to recognize and interact with other cell adhesion receptors on neighboring cells or with proteins of the extracellular matrix, respectively (1-3). E-cadherins belong to the family of integral membrane glycoproteins promoting homophylic calciumdependent cell-cell interactions and are well characterized adhesion receptors found within adherens-type junctions in epithelia. The extracellular domain of E-cadherins is able to mediate per se calcium-dependent homotypic interactions at sites of cell-cell contacts, while its highly conserved intracytoplasmic tail is involved in the strengthening of the homophylic adhesions by binding a set of related proteins called catenins which, in turn, link the complex to the actin cytoskeleton and elicit certain nuclear responses (4, 5). Recently, the dynamic aspects of cell adhesion and its relationship to physiological and pathophysiological events have been intensively investigated. They include cell growth and differentiation, cell recognition and sorting during developmental morphogenesis (reviewed in Ref.2), and a role in certain pathological processes, including the correlation betw...

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

“…E-cadherin is also implicated in regulation of signal transduction through other mediators including Rho family GTPases [43], phosphatidylinositol 3-kinase (PI3K) [44,45], and epidermal growth factor (EGF) receptor [45,46], whereas N-cadherin modulates fibroblast growth factor (FGF) receptor signaling [47] as well as the PI3K/Akt pathway [48,49]. Due to the diverse nature of these dynamic multimolecular interactions, cadherins are properly positioned to functionally integrate cellcell adhesion with regulation of signal transduction pathways and their associated transcriptional programs to control multiple aspects of cell shape and behavior.…”

E-cadherin-mediated Cell-Cell Attachment Activates Cdc42

“…E-cadherin-mediated cell adhesion was performed essentially as described previously (20). MCF-7 cells were grown to confluence in 60-mm culture dishes.…”

E-cadherin Homophilic Ligation Directly Signals through Rac and Phosphatidylinositol 3-Kinase to Regulate Adhesive Contacts

“…Taken together, these data indicated that PI 3-kinase activity, like Rac, was essential both for adhesion and for cells to extend their zones of adhesive contact after binding to hE/Fc. E-cadherin Ligation Recruits PI 3-Kinase to the Cell Surface-Pece et al (10) recently reported that the p85 subunit of type IA PI 3-kinase co-immunoprecipitated with E-cadherin as Madin-Darby canine kidney cell contacts were being reestablished after depletion of extracellular Ca 2ϩ . We observed a similar phenomenon in hE-CHO cell monolayers (not shown) and hypothesized that this might reflect direct recruitment of PI 3-kinase to E-cadherin in response to homophilic ligation.…”

“…PI 3-Kinase Signaling Is Necessary for Cadherin-based Adhesion-PI 3-kinase is a well documented upstream regulator of Rac (21)(22)(23)(24) and has recently been identified to associate with E-cadherin (10). To begin to assess the potential role of PI 3-kinase in cadherin signaling, we first tested whether PI 3-kinase activity was necessary for cadherin-specific adhesion.…”