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J. Biol. Chem., Vol. 283, Issue 6, 3519-3528, February 8, 2008

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

Chia-Ling Tu¹, Wenhan Chang, Zhongjian Xie^¶, and Daniel D. Bikle

From the Endocrine Unit, Veteran Affairs Medical Center, ^¶Northern California Institute for Research and Education and University of California, San Francisco, California 94121

Extracellular Ca²⁺ (Ca²⁺_o) is a critical regulator that promotes differentiation in epidermal keratinocytes. The calcium sensing receptor (CaR) is essential for mediating Ca²⁺ signaling during Ca²⁺_o-induced differentiation. Inactivation of the endogenous CaR-encoding gene CASR by adenoviral expression of a CaR antisense cDNA inhibited the Ca²⁺_o-induced increase in intracellular free calcium (Ca²⁺_i) and expression of terminal differentiation genes, while promoting apoptosis. Ca²⁺_o also instigates E-cadherin-mediated cell-cell adhesion, which plays a critical role in orchestrating cellular signals mediating cell survival and differentiation. Raising Ca²⁺_o concentration ([Ca²⁺]_o) from 0.03 to 2 mM rapidly induced the co-localization of -, β-, and p120-catenin with E-cadherin in the intercellular adherens junctions (AJs). To assess whether CaR is required for the Ca²⁺_o-induced activation of E-cadherin signaling, we examined the impact of CaR inactivation on AJ formation. Decreased CaR expression suppressed the Ca²⁺_o-induced AJ formation, membrane translocation, and the complex formation of E-cadherin, catenins, and the phosphatidylinositol 3-kinase (PI3K), although the expression of these proteins was not affected. The assembly of the E-cadherin-catenin-PI3K complex was sensitive to the pharmacologic inhibition of Src family tyrosine kinases but was not affected by inhibition of Ca²⁺_o-induced rise in Ca²⁺_i. Inhibition of CaR expression blocked the Ca²⁺_o-induced tyrosine phosphorylation of β-, -, and p120-catenin, PI3K, and the tyrosine kinase Fyn and the association of Fyn with E-cadherin and PI3K. Our results indicate that the CaR regulates cell survival and Ca²⁺_o-induced differentiation in keratinocytes at least in part by activating the E-cadherin/PI3K pathway through a Src family tyrosine kinase-mediated signaling.

Received for publication, October 5, 2007 , and in revised form, November 12, 2007.

^* This work was supported by a Merit Review Award from the Department of 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), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2089; Fax: 415-750-6929; E-mail: chia-ling.tu{at}ucsf.edu.

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