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

Abstract

and impairing differentiation in keratinocytes (8). One of the immediate cellular responses to Ca 2ϩo in epithelial cells is the formation of cell-cell contacts, a process mediated by the adhesion molecule E-cadherin (10). E-cadherin is a major classical cadherin in keratinocytes and is expressed throughout the epidermis (11). Upon Ca 2ϩ o stimulation, the extracellular portion of E-cadherin interacts with E-cadherin molecules on the surface of neighboring cells, whereas its cytoplasmic tail interacts with ␤-(or ␥-), ␣-, and p120-catenins to form the core adhesive structure of adherens junctions (AJ) (12). E-cadherin-mediated cell adhesion plays key roles in remodeling of epithelial cell-cell interaction and maintaining proper epidermal differentiation (10, 13). Loss of E-cadherin in the epidermis leads to a loss of AJ and impaired terminal differentiation (14). The sequential binding of catenins physically links E-cadherin to the actin cytoskeleton and other signaling molecules, including phosphatidylinositol 3-kinase (PI3K) (10, 15). Keratinocyte differentiation induced by Ca 2ϩ o necessitates the activation of PI3K. Pharmacological inhibition of PI3K blocks the expression of late differentiation markers and induces apoptosis in differentiating keratinocytes (16,17). Through interactions with the E-cadherin-catenin complex PI3K is recruited to the cell membrane, where it converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate in turn binds and activates PLC␥1 (17), which is required for maintaining the Ca Veterans Affairs and Grants PO1-AR39448, RO1-AR38386, and RO1-AG21353 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed: Endocrine Unit (111N

Structural and Functional Diversity of Desmosomes

“…This scenario predicted that adherens junction components or a different factor, perhaps the calcium receptor, CaR, responded to extracellular calcium by initiating intracellular calcium release (Tu et al, 2011;Xie & Bikle, 2007;Tu et al, 2007;Tu et al, 2008). Confi rming the involvement of intracellular calcium, Darier disease patients carrying a mutant form of the intracellular calcium pump, SERCA2, suffer from severe skin erosions attributed to desmosome loss (Sakuntabhai et al, 1999).…”

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…The CaSR coordinates these activities through regulation of a myriad of signaling pathways, including EGFR signaling, MAPK cascades and Ecadherin signaling [3,36,37,47,[50][51][52][62][63][64]. However, few studies have assessed the cell-or tissue-specificity of the cascades activated by engagement of the CaSR or determined the particular roles of the signaling cascades, leaving considerable room for discovery in this field.…”

“…Finally, CaSR signaling also has been implicated in regulating colonic epithelial cell differentiation and keratinocyte differentiation through the activation of E-cadherin signaling in a Rhodependent manner with filamin A involvement (Fig. 2) [62][63][64]. Chakrabarty and colleagues demonstrated that stimulation of the CaSR through extracellular calcium increased the expression of the tumor suppressor on colon carcinoma cells, and concomitantly reduced the activation of -catenin/T-cell factor, leading to the suppression of their malignant behavior [63].…”

The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on

“…The colocalisation of adherens junction proteins to secretory granules (Hodgkin et al 2007) suggests that the adherens junction may play a novel role in b-cell function, both in terms of b-cell proliferation (Carvell et al 2007) and insulin secretion (Hodgkin et al 2007, Rogers et al 2007. Neutralising ECAD-mediated cell adhesion decreases glucose-evoked synchronicity in Ca 2C signals between adjacent cells within islets (Rogers et al 2007) and evidence from human epidermal keratinocytes suggests that inactivation of the CaR suppresses the assembly of the ECAD-cateninphosphotidylinositol 3-kinase (PI3K) complex (Tu et al 2008). These data provide compelling evidence that the CaR influences multiple functions that ultimately regulate synchronicity of Ca 2C activity between b-cells within the islet and thus dramatically impinge on insulin secretion.…”