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

Abstract

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-␥1. In this study we sought to identify the upstream signaling pathway necessary for calcium activation of PI3K and its subsequent activation of phospholipase C-␥1. 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, ␤-catenin, or p120-catenin expression blocked calcium activation of PI3K and phospholipase C-␥1 and calcium-induced keratinocyte differentiation. However, knocking-down ␥-catenin expression had no effect. Calcium-induced PI3K recruitment to E-cadherin stabilized by p120-catenin at the plasma membrane requires ␤-catenin but not ␥-catenin. These data indicate that the recruitment of PI3K to the E-cadherin/␤-catenin/p120-catenin complex via ␤-catenin at the plasma membrane is required for calcium-induced phospholipase C-␥1 activation and, ultimately, keratinocyte differentiation.

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

“…Observations in our laboratory indicate that in SKOV3 ovarian carcinoma cells forced to grow in suspension E-cadh expression have increased, possibly contributing to escape from anoikis (Miotti, S, unpublished data). These observations and a recent comment by Ahmed et al (2007), together with the present data, support the notion that EOC cells require E-cadh for growth, and argue against the previously proposed suppressive role of E-cadh in transformed ovarian cells, which behave more similarly to normal cells, that is, keratinocytes (Xie and Bikle, 2007) and Madison Darby canine kidney cells (Pece et al, 1999).…”

“…On cell-cell contact formation, E-cadh has been proposed as a 'relationship molecule' between extra and intracellular environments leading to PI3K/AKT activation in normal cells (Pece et al, 1999;Woodfield et al, 2001). E-cadh-mediated cell-cell contacts induce both associations with the PI3K complex and the phospholipase C-g activation in keratinocytes, thus leading to keratinocyte differentiation (Xie and Bikle, 2007). By contrast, in tumor cells, E-cadh expression is lost and E-cadh ectopic expression inhibits invasiveness and growth in a cell-cell adhesion-independent manner (Wong and Gumbiner, 2003).…”

“…E-cadh was initially considered a structural protein; however, recent evidence suggests a role for E-cadh in transducing outside-in signals. In normal keratinocytes, such E-cadh-activated signaling pathway appears to involve the phosphoinositide-3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT (Calautti et al, 2005;Xie and Bikle, 2007).…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…An increase in extracellular Ca 2 ϩ concentration activates a Ca 2 ϩ -sensing receptor (CaR), a G-protein-coupled receptor (Tu et al, 2001), and causes a rapid and sustained increase in intracellular Ca 2 ϩ concentration (Sharpe et al, 1989). This intracellular increase in Ca 2 ϩ concentration is linked to activation of phospholipase C and inositol phospholipid turnover and the production of both diacylglycerol and inositol 1,4,5-trisphosphate (IP3; Xie & Bikle 2007), and activation of protein kinase C (PKC) in keratinocytes (Nagao et al, 1989;Sheu et al, 1989). Concerning PKC, it should be noted that PKC appears to play an important role in 272 Y. KITAJIMA dynamic disassembly and assembly also during wound healing (Wallis et al, 2000;Thomason et al, 2012).…”

In Serum, Higher Parathyroid Hormone but Not Lower Vitamin D Is Associated with Oral Squamous Cell Carcinoma

“…We previously demonstrated that high extracellular calcium triggers differentiation of keratinocytes by inducing the formation of the p120-catenin-dependent E-cadherinbeta-catenin complex [7][8][9] . Lajolo et al 33 showed that mice fed a diet containing 0.12 g calcium glucarate daily had a reduced rate of oral tumours.…”