Abstract
Zinc is an essential trace element participating in diverse biological processes. Cellular zinc levels are strictly controlled by two families of transport proteins: ZIP channels (SLC39A) and ZnT transporters (SLC30A). ZIP channels increase cytosolic zinc levels by importing zinc into cells or releasing zinc from intracellular stores such as the ER. Among all the 14 human members of the ZIP family, ZIP7 is a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation on residues S275 and S276, resulting in activation of multiple downstream pathways. Employing site-directed mutagenesis, we investigated the importance of these individual serine residues as well as other predicted phosphorylation sites on ZIP7, showing that all four sites are required for maximal ZIP7 activation. Using phosphor-protein arrays, we also discovered the major signalling pathways that were activated as a direct result of ZIP7-mediated zinc release from intracellular stores. These data reveal the role of ZIP7-mediated zinc release from intracellular stores in driving major pathways, such as MAPK, mTOR and PI3K-AKT, involved in providing cell survival and proliferation and often over activated in cancer.
Highlights
ZIP channels are involved in controlling intracellular zinc levels
We investigate the activation of ZIP7-mediated zinc release, and its downstream consequences on signalling pathways such as PI3K-AKT, mitogen-activated protein kinases (MAPK) and mTOR
Employing site-directed mutagenesis, we investigated the importance of these individual serine residues as well as other predicted phosphorylation sites on ZIP7, showing that all four sites are required for maximal ZIP7 activation
Summary
Activation of different tyrosine kinase pathways through the inhibitory action of zinc on protein tyrosine phosphatases.[6]. Metallomics behaviour of breast cancer cells that have acquired tamoxifen resistance.[14] the increased activation of these kinases in these tamoxifen-resistant cells has been attributed to increased activation of ZIP7 and the subsequent higher level of intracellular zinc,[10] linking ZIP7 to the mechanism of acquiring tamoxifen resistance in breast cancer.[15] given the ubiquitous expression of ZIP7 in the human body,[16] its location on ER zinc stores,[16,17] and its activation mechanism by phosphorylation,[5] ZIP7 has been suitably designated as ‘‘a hub for tyrosine kinase activation’’.18 In light of this information, we developed a monoclonal antibody that recognises ZIP7 when phosphorylated on residues S275 and S276 and are using this to determine the downstream targets of ZIP7-mediated zinc release. This data reveals new downstream targets of ZIP7-mediated zinc release and explains its role in driving cell proliferation and survival
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