Protein kinase CK2 opens the gate for zinc signaling

The importance of zinc in biology is evidenced by the growing number of disease states that directly involve aberrant levels of zinc, including neurodegeneration, inflammation, diabetes, cancer and more. Zinc is a component of an estimated 10% of all proteins and has a well-established role in regulation of gene expression, primarily through activation of metalresponsive transcription factor-1 (MTF1) as well as an array of trans-acting factors. Recently, attention has been drawn to the fact that free Zn in cells has also non-genomic signaling effects that can be evoked through extracellular stimuli. The Zn ion therefore fulfils the criteria for being a second messenger. However, delivery of its second messenger role would require three key components to be present: (1) transmission of the extracellular stimuli to the intracellular machinery, (2) mechanism for the gated release of Zn into the cytosol through modification of an effector molecule and (3) the translation of Zn flux into altered activity in downstream targets. Our recent finding that a zinc channel, ZIP7 (SLC39A7), can be activated by phosphorylation by protein kinase CK2 as a direct result of an extracellular stimulation provides the central component of this pathway. ZIP7 is the only ZIP zinc channel known to reside in the membrane of the endoplasmic reticulum. In response to epidermal growth factor (EGF) stimulation, CK2 activates ZIP7 through serine phosphorylation, resulting in release of free Zn ions into the cytosol. The consequential rise in cytosolic Zn concentration activates protein kinases involved Protein kinase CK2 opens the gate for zinc signaling