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Vol. 20, Issue 6, 1695-1704, March 15, 2009

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Phosphatidylinositol-4-phosphate 5-kinase 1 Mediates Extracellular Calcium-induced Keratinocyte Differentiation

Zhongjian Xie^*, Sandra M. Chang^*, Sally D. Pennypacker^*, Er-Yuan Liao, and Daniel D. Bikle^*

*Endocrine Unit, Veterans Affairs Medical Center, Northern California Institute for Research and Education and University of California at San Francisco, San Francisco, CA 94121; and Institute of Metabolism and Endocrinology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan 410011, China

Submitted July 24, 2008; Revised January 2, 2009; Accepted January 12, 2009
Monitoring Editor: Carole Parent

Extracellular calcium (Cao) is a major regulator of keratinocyte differentiation, but the mechanism is unclear. Phosphatidylinositol-4-phosphate 5-kinase 1 (PIP5K1) is critical in synthesizing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. In this study, we sought to determine whether PIP5K1 plays a role in mediating the ability of Cao to induce keratinocyte differentiation. We found that treatment of human keratinocytes in culture with Cao resulted in increased PIP5K1 level and activity, as well as PI(4,5)P₂ level, binding of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P₃] to and activation of phospholipase C-1 (PLC-1), with the resultant increase in inositol 1,4,5-trisphosphate (IP₃) and intracellular calcium (Cai). Knockdown of PIP5K1 in human keratinocytes blocked Cao-induced increases in the binding of PI(3,4,5)P₃ to PLC-1; PLC-1 activity; levels of PI(4,5)P₂, IP₃, and Cai; and induction of keratinocyte differentiation markers. Coimmunoprecipitation and confocal studies revealed that Cao stimulated PIP5K1 recruitment to the E-cadherin–catenin complex in the plasma membrane. Knockdown of E-cadherin or β-catenin blocked Cao-induced activation of PIP5K1. These results indicate that after Cao stimulation PIP5K1 is recruited by the E-cadherin–catenin complex to the plasma membrane where it provides the substrate PI(4,5)P₂ for both PI3K and PLC-1. This signaling pathway is critical for Cao-induced generation of the second messengers IP₃ and Cai and keratinocyte differentiation.

Address correspondence to: Zhongjian Xie (zhongjian.xie{at}ucsf.edu)

Abbreviations used: Cai, intracellular calcium; Cao, extracellular calcium; DAG, diacylglycerol; IP₃, inositol 1,4,5-trisphosphate; PI(3,4,5)P₃, phosphatidylinositol 3,4,5-triphosphate; PI3K, phosphatidylinositol 3-kinase; PIP5K1, phosphatidylinositol 4-phosphate 5-kinase 1; PI4P, phosphatidylinositol 4-phosphate; PI(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C.

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