Interaction between protein kinase C and regulatory ligand is enhanced by a chelatable pool of cellular zinc

Forbes, Ian J.; Zalewski, Peter D.; Giannakis, C.; Petkoff, Helen S.; Cowled, Prue

doi:10.1016/0167-4889(90)90001-t

Cited by 60 publications

(19 citation statements)

References 25 publications

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“…However, zinc has also been shown to affect PKC activity in platelets and lymphocytes, by increasing association with the cell membrane. 28 Additionally, the biphasic aggregometry response to zinc indicates a role for granule release in full activation, further implicating PKC in zinc-induced aggregation. 29 This is further supported by the observation that combined inhibition of P2Y12, P2X1 and thromboxane signalling results in partial aggregation following zinc treatment (an inhibition-resistant activation profile) demonstrating elements of an activatory response that are independent of granule release.…”

Section: Discussionmentioning

confidence: 99%

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

et al. 2016

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Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbβ3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2β1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.

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Section: Discussionmentioning

confidence: 99%

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

et al. 2016

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“…Certain isoforms of protein kinase C (PKC) appear to be required for this redistribution (2,3,32,33,59). Zinc stimulates both membrane localization and activity of PKC (13,17,18,28,54,69). Thus PKC represents a fourth step at which zinc promotes insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In liver cells, total extractable zinc ranged from 264 to 415 mol/kg wet wt in fasting and fed states (4), ϳ300-450 M. Assuming that 70-80% of that intracellular zinc was tightly bound (i.e., chelator insensitive, see Ref. 18), that still leaves micromolar concentrations of zinc available to interact with mTOR. In Erlich and Yoshida cells, "labile" Zn 2ϩ was determined to be ϳ100 M (1).…”

Section: Discussionmentioning

confidence: 99%

Zinc stimulates the activity of the insulin- and nutrient-regulated protein kinase mTOR

Lynch

Patson

Goodman

et al. 2001

American Journal of Physiology-Endocrinology and Metabolism

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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 microM Zn2+ in the presence of an excess of either Mn2+ or Mg2+, whereas incubation with 1,10-phenanthroline had no effect. These findings indicate that Zn2+ regulates, but is not absolutely required for, mTOR protein kinase activity. Zinc also stimulated a recombinant human form of mTOR. The stimulatory effects of Zn2+ were maximal at approximately 100 microM but decreased and became inhibitory at higher physiologically irrelevant concentrations. Micromolar concentrations of other divalent cations, Ca2+, Fe2+, and Mn2+, had no effect on the protein kinase activity of mTOR in the presence of excess Mg2+. 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 Zn2+ on these steps may thereby promote insulin and nutritional signaling.

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“…Our observation that zinc counteracts the effect of cAMP on glycolysis as catalyzed by protein kinase A is in line with the concept that Zn 2ϩ plays a regulatory role in signal transduction. For instance, zinc has been shown to induce the translocation of protein kinase C to membranes that will convert the enzyme into a more active form due to binding of zinc to the cysteine-rich domains required for the formation of the phorbol ester binding site (38,39). In Chinese hamster ovary cells overexpressing protein kinase C ␣ , phorbol ester activation led to an increased phosphorylation of the insulin receptor.…”

Section: On Metabolite Concentration Of Hepatocytes In the Presence Amentioning

confidence: 99%

Intracellular Zinc Movement and Its Effect on the Carbohydrate Metabolism of Isolated Rat Hepatocytes

Brand

Kleineke

1996

Journal of Biological Chemistry

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The effect of zinc ions on carbohydrate metabolism and intracellular Zn2+ was studied in hepatocytes from fed rats. The addition of ZnCl2 to the medium led to an almost 3-fold increase in lactate production and an increase in net glucose production of about 50%. Half-maximal rates occurred at about 40 microM ZnCl2. These effects were not seen with Mn2+, Co2+, or Ni2+ up to 80 microM, whereas Cu2+ at 80 microM and Cd2+ or Pb2+ at 8 microM exhibited similar effects as 80 microM ZnCl2. Changes in intracellular Zn2+ were followed by single cell epifluorescence using zinquin as a specific probe. Intracellular free Zn2+ in isolated hepatocytes was 1.26 +/- 0.27 microM, and the addition of ZnCl2 led to a concentration-dependent increase in epifluorescence. CdCl2 or PbCl2 at 8 microM was as potent as ZnCl2 at 20-80 microM, whereas NiCl2 at 80 microM was without effect. ZnCl2 completely abolished the inhibition of glycolysis by glucagon (cAMP). Glucagon led to a pronounced drop in cytosolic Zn2+. Both glucagon and zinc stimulated glycogenolysis by increasing the phosphorylation of glycogen phosphorylase but acted oppositely on glycolysis. Zinc overcame the inactivation of pyruvate kinase by glucagon without changing the hormone-induced protein phosphorylation. The antagonistic action of zinc and cAMP on glycolysis together with the rapid and marked decrease in free zinc concentration induced by glucagon (cAMP) may indicate an as yet unknown role of zinc as an important mediator of regulation of carbohydrate metabolism.

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Interaction between protein kinase C and regulatory ligand is enhanced by a chelatable pool of cellular zinc

Cited by 60 publications

References 25 publications

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

Zinc stimulates the activity of the insulin- and nutrient-regulated protein kinase mTOR

Intracellular Zinc Movement and Its Effect on the Carbohydrate Metabolism of Isolated Rat Hepatocytes

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