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J. Biol. Chem., Vol. 275, Issue 21, 16242-16250, May 26, 2000

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Novel Function of Phosphoinositide 3-Kinase in T Cell Ca²⁺ Signaling
A PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE-MEDIATED Ca²⁺ ENTRY MECHANISM^*

Ao-Lin Hsu, Tsui-Ting Ching, Goutam Sen^§, Da-Sheng Wang, Subbarao Bondada^§, Kalwant S. Authi^¶, and Ching-Shih Chen

From the  Division of Pharmaceutical Sciences, College of Pharmacy and ^§ Department of Microbiology and Immunology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536 and ^¶ Platelet Section, Thrombosis Research Institute, Chelsea, London SW3 6LR, United Kingdom

This study presents evidence that phosphoinositide (PI) 3-kinase is involved in T cell Ca²⁺ signaling via a phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P₃-sensitive Ca²⁺ entry pathway. First, exogenous PI(3,4,5)P₃ at concentrations close to its physiological levels induces Ca²⁺ influx in T cells, whereas PI(3,4)P₂, PI(4,5)P₂, and PI(3)P have no effect on [Ca²⁺]_i. This Ca²⁺ entry mechanism is cell type-specific as B cells and a number of cell lines examined do not respond to PI(3,4,5)P₃ stimulation. Second, inhibition of PI 3-kinase by wortmannin and by overexpression of the dominant negative inhibitor p85 suppresses anti-CD3-induced Ca²⁺ response, which could be reversed by subsequent exposure to PI(3,4,5)P₃. Third, PI(3,4,5)P₃ is capable of stimulating Ca²⁺ efflux from Ca²⁺-loaded plasma membrane vesicles prepared from Jurkat T cells, suggesting that PI(3,4,5)P₃ interacts with a Ca²⁺ entry system directly or via a membrane-bound protein. Fourth, although D-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P₄) mimics PI(3,4,5)P₃ in many aspects of biochemical functions such as membrane binding and Ca²⁺ transport, we raise evidence that Ins(1,3,4,5)P₄ does not play a role in anti-CD3- or PI(3,4,5)P₃-mediated Ca²⁺ entry. This PI(3,4,5)P₃-stimulated Ca²⁺ influx connotes physiological significance, considering the pivotal role of PI 3-kinase in the regulation of T cell function. Given that PI 3-kinase and phospholipase C- form multifunctional complexes downstream of many receptor signaling pathways, we hypothesize that PI(3,4,5)P₃-induced Ca²⁺ entry acts concertedly with Ins(1,4,5)P₃-induced Ca²⁺ release in initiating T cell Ca²⁺ signaling. By using a biotinylated analog of PI(3,4,5)P₃ as the affinity probe, we have detected several putative PI(3,4,5)P₃-binding proteins in T cell plasma membranes.

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