PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation.
Free zinc ions (Zn(2+)) participate in several signaling pathways. The aim of the present study was to investigate a potential involvement of Zn(2+) 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 Zn(2+) into the cytoplasm activates ERK1/2, but not STAT5. In the present study, Akt phosphorylation in response to IL-2 was abrogated by the Zn(2+) chelator N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, and was induced by treatment with Zn(2+) 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 Zn(2+)in vitro yielded an IC50 of 0.59 nM. Considering a resting free cytoplasmic Zn(2+) level of 0.2 nM in the T-cell line CTLL-2, this seems ideally suited for dynamic regulation by cellular Zn(2+). Oxidation with H2O2 and supplementation with Zn(2+) led to similar changes in the CD spectrum of PTEN. Moreover, Zn(2+) 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.
Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. HHaase@ukaachen.de.
Laura Marie
LM
Plum
Anne
A
Brieger
Gabriela
G
Engelhardt
Silke
S
Hebel
Andreas
A
Nessel
Marcus
M
Arlt
Jennifer
J
Kaltenberg
Ulrich
U
Schwaneberg
Michael
M
Huber
Lothar
L
Rink
Hajo
H
Haase
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D007376:Interleukin-2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D015032:Zinc