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The Recruitment of Phosphatidylinositol 3-Kinase to the E-cadherin-Catenin Complex at the Plasma Membrane Is Required for Calcium-induced Phospholipase C-γ1 Activation and Human Keratinocyte Differentiation*

Calcium induces epidermal keratinocyte differentiation, but the mechanism is not completely understood. We have previously demonstrated that calcium-induced human keratinocyte differentiation requires an intracellular calcium rise caused by phosphatidylinositol 3-kinase (PI3K)-dependent activation of phospholipase C-γ1. In this study we sought to identify the upstream signaling pathway necessary for calcium activation of PI3K and its subsequent activation of phospholipase C-γ1. We found that calcium induces the recruitment of PI3K to the E-cadherin-catenin complex at the plasma membrane of human keratinocytes. Knocking-down E-cadherin, β-catenin, or p120-catenin expression blocked calcium activation of PI3K and phospholipase C-γ1 and calcium-induced keratinocyte differentiation. However, knocking-down γ-catenin expression had no effect. Calcium-induced PI3K recruitment to E-cadherin stabilized by p120-catenin at the plasma membrane requires β-catenin but not γ-catenin. These data indicate that the recruitment of PI3K to the E-cadherin/β-catenin/p120-catenin complex via β-catenin at the plasma membrane is required for calcium-induced phospholipase C-γ1 activation and, ultimately, keratinocyte differentiation.