In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 281, No. 1 ( 2001-07-01), p. E25-E34
Abstract:
Recent studies indicate that zinc activates p70 S6 kinase (p70 S6k ) by a mechanism involving phosphatidylinositol 3-kinase (PI 3-kinase) and Akt (protein kinase B). Here it is shown that phenanthroline, a zinc and heavy metal chelator, inhibited both amino acid- and insulin-stimulated phosphorylation of p70 S6k . Both amino acid and insulin activations of p70 S6k involve a rapamycin-sensitive step that involves the mammalian target of rapamycin (mTOR, also known as FRAP and RAFT). However, in contrast to insulin, amino acids activate p70 S6k by an unknown PI 3-kinase- and Akt-independent mechanism. Thus the effects of chelator on amino acid activation of p70 S6k were surprising. For this reason, we tested the hypothesis that zinc directly regulates mTOR activity, independently of PI 3-kinase activation. In support of this, basal and amino acid stimulation of p70 S6k phosphorylation was increased by zinc addition to the incubation media. Furthermore, the protein kinase activities of mTOR immunoprecipitated from rat brain lysates were stimulated two- to fivefold by 10–300 μM Zn 2+ in the presence of an excess of either Mn 2+ or Mg 2+ , whereas incubation with 1,10-phenanthroline had no effect. These findings indicate that Zn 2+ regulates, but is not absolutely required for, mTOR protein kinase activity. Zinc also stimulated a recombinant human form of mTOR. The stimulatory effects of Zn 2+ were maximal at ∼100 μM but decreased and became inhibitory at higher physiologically irrelevant concentrations. Micromolar concentrations of other divalent cations, Ca 2+ , Fe 2+ , and Mn 2+ , had no effect on the protein kinase activity of mTOR in the presence of excess Mg 2+ . Our results and the results of others suggest that zinc acts at multiple steps in amino acid- and insulin cell-signaling pathways, including mTOR, and that the additive effects of Zn 2+ on these steps may thereby promote insulin and nutritional signaling.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.2001.281.1.E25
Language:
English
Publisher:
American Physiological Society
Publication Date:
2001
detail.hit.zdb_id:
1477331-4
SSG:
12
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