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J. Biol. Chem., Vol. 276, Issue 34, 31831-31838, August 24, 2001

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Phosphatidylinositol 3-Kinase-dependent Extracellular Calcium Influx Is Essential for CX₃CR1-mediated Activation of the Mitogen-activated Protein Kinase Cascade^*

Vikram Kansra, Christopher Groves^§, Jose Carlos Gutierrez-Ramos^§, and Roberto D. Polakiewicz^¶

From  Cell Signaling Technology, Beverly, Massachusetts 01915 and ^§ Millennium Pharmaceuticals, Cambridge, Massachusetts 02139

Fractalkine, the first member of the CX₃C chemokine family, induces leukocyte chemotaxis through activation of its high affinity receptor, CX₃CR1. Like other chemokine receptors, CX₃CR1 is coupled to a pertussis toxin-sensitive heterotrimeric G_i protein, which is necessary for rapid rise in the concentration of intracellular calcium. Using a Chinese hamster ovary cell line stably transfected with the CX₃CR1 receptor, we show that the source of calcium mobilized by fractalkine stimulation is the extracellular pool. Calcium influx is blocked by extracellular calcium chelators, as well as by divalent heavy metals such as Ni²⁺, Co²⁺, and Cd²⁺ without affecting the integrity of intracellular stores. Remarkably, selective phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin and LY294002, abolish the wave extracellular calcium, suggesting that an active PI3K is necessary for this event. The influx of extracellular calcium is in turn required to trigger the activation of the p42/44 mitogen-activated protein/extracellular signal-regulated kinase pathway, but is not necessary for other signals downstream to PI3K, such as phosphorylation of Akt. The potential role of this signaling cascade in fractalkine-mediated chemotaxis is discussed.

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