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J. Biol. Chem., Vol. 282, Issue 12, 8695-8703, March 23, 2007

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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-1 Activation and Human Keratinocyte Differentiation^*

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

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.

Received for publication, September 26, 2006 , and in revised form, December 11, 2006.

^* This work was supported by NIAMS, National Institutes of Health Grant P01AR39448. 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, Veterans Affairs Medical Center, 4150 Clement St. (111N), San Francisco, CA 94121. Tel.: 415-750-2089; Fax: 415-750-6929; E-mail: Zhongjian.Xie{at}ucsf.edu.

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				Z. Xie, S. M. Chang, S. D. Pennypacker, E.-Y. Liao, and D. D. Bikle Phosphatidylinositol-4-phosphate 5-kinase 1{alpha} Mediates Extracellular Calcium-induced Keratinocyte Differentiation Mol. Biol. Cell, March 15, 2009; 20(6): 1695 - 1704. [Abstract] [Full Text] [PDF]

				C.-L. Tu, W. Chang, Z. Xie, and D. D. Bikle Inactivation of the Calcium Sensing Receptor Inhibits E-cadherin-mediated Cell-Cell Adhesion and Calcium-induced Differentiation in Human Epidermal Keratinocytes J. Biol. Chem., February 8, 2008; 283(6): 3519 - 3528. [Abstract] [Full Text] [PDF]