title: Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling.
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.
authors.affiliation: Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK. taylorkm@cardiff.ac.uk.
authors.forename: T
authors.initials: T
authors.lastname: Nimmanon
authors.forename: S
authors.initials: S
authors.lastname: Ziliotto
authors.forename: S
authors.initials: S
authors.lastname: Morris
authors.forename: L
authors.initials: L
authors.lastname: Flanagan
authors.forename: K M
authors.initials: KM
authors.lastname: Taylor
mesh_terms: D027682:Cation Transport Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D015032:Zinc; C102227:SLC39A7 protein, human; C546842:MTOR protein, human