Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 7 February 2012
Vol. 5, Issue 210, p. ra11
[DOI: 10.1126/scisignal.2002585]

RESEARCH ARTICLES

Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7

Kathryn M. Taylor1*, Stephen Hiscox1, Robert I. Nicholson1, Christer Hogstrand2{dagger}, and Peter Kille3{dagger}

1 Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VIIth Avenue, Cardiff CF10 3NB, UK.
2 Metals Metabolism Group, Diabetes and Nutritional Sciences Division, King’s College London, 3.85 Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
3 Department of Biosciences, Cardiff University, Main Building, Museum Avenue, Cardiff CF10 3AT, UK.

{dagger} These authors contributed equally to this work.

Abstract: The transition element zinc, which has recently been identified as an intracellular second messenger, has been implicated in various signaling pathways, including those leading to cell proliferation. Zinc channels of the ZIP (ZRT1- and IRT1-like protein) family [also known as solute carrier family 39A (SLC39A)] transiently increase the cytosolic free zinc (Zn2+) concentration in response to extracellular signals. We show that phosphorylation of evolutionarily conserved residues in endoplasmic reticulum zinc channel ZIP7 is associated with the gated release of Zn2+ from intracellular stores, leading to activation of tyrosine kinases and the phosphorylation of AKT and extracellular signal–regulated kinases 1 and 2. Through pharmacological manipulation, proximity ligation assay, and mutagenesis, we identified protein kinase CK2 as the kinase responsible for ZIP7 activation. Together, the present results show that transition element channels in eukaryotes can be activated posttranslationally by phosphorylation, as part of a cell signaling cascade. Our study links the regulated release of zinc from intracellular stores to phosphorylation of kinases involved in proliferative responses and cell migration, suggesting a functional role for ZIP7 and zinc signals in these events. The connection with proliferation and migration, as well as the activation of ZIP7 by CK2, a kinase that is antiapoptotic and promotes cell division, suggests that ZIP7 may provide a target for anticancer drug development.

* To whom correspondence should be addressed. E-mail: taylorkm{at}cardiff.ac.uk

Citation: K. M. Taylor, S. Hiscox, R. I. Nicholson, C. Hogstrand, P. Kille, Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7. Sci. Signal. 5, ra11 (2012).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Plasma zinc's alter ego is a low-molecular-weight humoral factor.
O. Ou, K. Allen-Redpath, D. Urgast, M.-J. Gordon, G. Campbell, J. Feldmann, G. F. Nixon, C.-D. Mayer, I.-S. Kwun, and J. H. Beattie (2013)
FASEB J 27, 3672-3682
   Abstract »    Full Text »    PDF »
Zinc Biochemistry: From a Single Zinc Enzyme to a Key Element of Life.
W. Maret (2013)
Adv Nutr 4, 82-91
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 7 February 2012.
K. M. Taylor and A. M. VanHook (2012)
Science Signaling 5, pc3
   Abstract »    Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882