Zn(2+) influx activates ERK and Akt signaling pathways.

Zinc (Zn(2+)) is an essential metal in biology, and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn(2+) that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn(2+) dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn(2+) impact kinase signaling pathways. By simultaneously monitoring Zn(2+) dynamics and kinase activity in individual cells, we quantify changes in labile Zn(2+) and directly correlate changes in Zn(2+) with ERK and Akt activity. Under our experimental conditions, Zn(2+) fluctuations are not toxic and do not activate stress-dependent kinase signaling. We demonstrate that while Zn(2+) can nonspecifically inhibit phosphatases leading to sustained kinase activation, ERK and Akt are predominantly activated via upstream signaling and through a common node via Ras. We provide a framework for quantification of Zn(2+) fluctuations and correlate these fluctuations with signaling events in single cells to shed light on the role that Zn(2+) dynamics play in healthy cell signaling.