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Issue 7, 2014
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PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation

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Abstract

Free zinc ions (Zn2+) participate in several signaling pathways. The aim of the present study was to investigate a potential involvement of Zn2+ in the PI3K/Akt pathway of interleukin (IL)-2 signaling in T-cells. The IL-2 receptor triggers three major pathways, ERK1/2, JAK/STAT5, and PI3K/Akt. We have previously shown that an IL-2-mediated release of lysosomal Zn2+ into the cytoplasm activates ERK1/2, but not STAT5. In the present study, Akt phosphorylation in response to IL-2 was abrogated by the Zn2+ chelator N,N,N′,N′-tetrakis-2(pyridyl-methyl)ethylenediamine, and was induced by treatment with Zn2+ and the ionophore pyrithione. The latter were ineffective in cells that were treated with siRNA against the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that degrades the lipid second messenger PI(3,4,5)P3, which is produced by PI3K and leads to activation of Akt. Inhibition of recombinant PTEN by Zn2+in vitro yielded an IC50 of 0.59 nM. Considering a resting free cytoplasmic Zn2+ level of 0.2 nM in the T-cell line CTLL-2, this seems ideally suited for dynamic regulation by cellular Zn2+. Oxidation with H2O2 and supplementation with Zn2+ led to similar changes in the CD spectrum of PTEN. Moreover, Zn2+ partially prevented the oxidation of cysteines 71 and 124. Hence, we hypothesize that zinc signals affect the IL-2-dependent PI3K/Akt pathway by inhibiting the negative regulator PTEN through binding with a sub-nanomolar affinity to cysteine residues that are essential for its catalytic activity.

Graphical abstract: PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation

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Publication details

The article was received on 16 Jul 2013, accepted on 08 Apr 2014 and first published on 09 Apr 2014


Article type: Paper
DOI: 10.1039/C3MT00197K
Citation: Metallomics, 2014,6, 1277-1287

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    PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation

    L. M. Plum, A. Brieger, G. Engelhardt, S. Hebel, A. Nessel, M. Arlt, J. Kaltenberg, U. Schwaneberg, M. Huber, L. Rink and H. Haase, Metallomics, 2014, 6, 1277
    DOI: 10.1039/C3MT00197K

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