Recruitment of Phosphoinositide 3-Kinase Defines a Positive Contribution of Tyrosine Kinase Signaling to E-cadherin Function

Abstract

Classical cadherin adhesion molecules can function as adhesion-activated cell-signaling receptors. One key target for cadherin signaling is the lipid kinase phosphoinositide (PI) 3-kinase, which is recruited to cell-cell contacts and activated by E-cadherin. In this study, we sought to identify upstream factors necessary for E-cadherin to activate PI 3-kinase signaling. We found that inhibition of tyrosine kinase signaling blocked recruitment of PI 3-kinase to E-cadherin contacts and abolished the ability of E-cadherin to activate PI 3-kinase signaling. Tyrosine kinase inhibitors further perturbed several parameters of cadherin function, including cell adhesion and the ability of cells to productively extend nascent cadherin-adhesive contacts. Notably, the functional effects of tyrosine kinase blockade were rescued by expression of a constitutively active form of PI 3-kinase that restores PI 3-kinase signaling. Finally, using dominant negative Src mutants and Src-null cells, we identified Src as one key upstream kinase in the E-cadherin/PI 3-kinase-signaling pathway. Taken together, our findings indicate that tyrosine kinase activity, notably Src signaling, can contribute positively to cadherin function by supporting E-cadherin signaling to PI 3-kinase.

E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

“…Such E-cadhactivated PI3K cascade has a clear impact on cadh function, as it is required for adhesive strengthening and for the efficient assembly of cadh-based adhesive contacts. More recently, there is evidence that upstream signaling from RTKs and src family kinases upregulates adhesive cadherin function (Pang et al, 2005;.…”

Gab2 and Src co-operate in human mammary epithelial cells to promote growth factor independence and disruption of acinar morphogenesis

“…This is intriguing in light of reports that depending on context, PI3-kinase signalling can play positive or negative roles in the formation of E-cadherin-based adherens junctions. Thus, while PI3-kinase signalling enhances the formation of nascent adhesive contacts following E-cadherin homophilic ligation (Kovacs et al, 2002;Pang et al, 2005), in v-Src-expressing MDCK cells it promotes junctional instability, since cell-cell aggregation can be induced in an E-cadherin-dependent manner by expressing PTEN (Kotelevets et al, 2001). These contrasting effects are probably explained by marked differences in signal strength and duration.…”

Inactivation of the Calcium Sensing Receptor Inhibits E-cadherin-mediated Cell-Cell Adhesion and Calcium-induced Differentiation in Human Epidermal Keratinocytes

“…Many studies have demonstrated that tyrosine kinase activity is necessary for the assembly of AJ and the interaction of PI3K with the E-cadherin-catenin complex. Pharmacological inhibition of tyrosine kinase perturbs the formation of AJ and prevents activation of PI3K by Ca 2ϩ o (16,22,23). In differentiating mouse keratinocytes, Ca 2ϩ o -induced assembly of E-cadherin-catenin complex and the recruitment of PI3K to E-cadherin are accompanied by tyrosine phosphorylation of ␤-, ␥-, and p120-catenin (22).…”