Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling

Nimmanon, Thirayost; Ziliotto, Silvia; Morris, Sue; Flanagan, Liam; Taylor, KM

doi:10.1039/c6mt00286b

Cited by 77 publications

(86 citation statements)

References 41 publications

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“…In contrast, it would be interesting to further study the role of Zip7. This transporter is activated by extracellular zinc entry and increases zinc levels in the cytosol by transporting zinc out of the endoplasmic reticulum (6). Our experiments showed that Zip7 is upregulated in activated Jurkat cells and mouse T cells.…”

Section: Discussionmentioning

confidence: 59%

“…At the molecular level, besides being a structural component of many proteins, zinc has also been shown to be a second messenger. Thus, zinc movements influence signaling cascades by regulating key enzymes such as AKT and GSK-3 (6,7), as well as transcription programs by acting on transcription factors such as MTF-1 and NF-кB (8,9). In this dynamic scenario, several transporters and zinc binding proteins work in a coordinated way to tightly regulate cytosolic zinc concentrations.…”

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confidence: 99%

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Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

Colomar-Carando

Meseguer

Company-Garrido

et al. 2019

The Journal of Immunology

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Zinc deficiency causes immune dysfunction. In T lymphocytes, hypozincemia promotes thymus atrophy, polarization imbalance, and altered cytokine production. Zinc supplementation is commonly used to boost immune function to prevent infectious diseases in at-risk populations. However, the molecular players involved in zinc homeostasis in lymphocytes are poorly understood. In this paper, we wanted to determine the identity of the transporter responsible for zinc entry into lymphocytes. First, in human Jurkat cells, we characterized the effect of zinc on proliferation and activation and found that zinc supplementation enhances activation when T lymphocytes are stimulated using anti-CD3/anti-CD28 Abs. We show that zinc entry depends on specific pathways to correctly tune the NFAT, NF-κB, and AP-1 activation cascades. Second, we used various human and murine models to characterize the zinc transporter family, Zip, during T cell activation and found that Zip6 was strongly upregulated early during activation. Therefore, we generated a Jurkat Zip6 knockout (KO) line to study how the absence of this transporter affects lymphocyte physiology. We found that although Zip6KO cells showed no altered zinc transport or proliferation under basal conditions, under activation, these KO cells showed deficient zinc transport and a drastically impaired activation program. Our work shows that zinc entry into activated lymphocytes depends on Zip6 and that this transporter is essential for the correct function of the cellular activation machinery.

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

Colomar-Carando

Meseguer

Company-Garrido

et al. 2019

The Journal of Immunology

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“…A strong collaboration between zinc signaling and protein phosphorylation is clear from the actions of zinc as a second messenger in different cell types leading to the activation of various phosphorylation cascades, and the inhibition of protein tyrosine phosphatase (PTP) activity [20,21]. PTPs play central roles in cellular function as key regulators of protein phosphorylation, directly affecting the activity of a great number of phosphoproteins and tyrosine kinase pathways [110][111][112][113][114]. PTPs contain a substrate binding site (in the P-loop) binding the phosphate ester group of the substrate and an active site (in the protein loop known as the WPDloop due to the conserved tryptophan-proline-aspartic acid sequence).…”

Section: Zinc and Protein Tyrosine Phosphatasesmentioning

confidence: 99%

“…Phosphorylation of hZIP7 was linked to the release of Zn 2+ ions from intracellular stores which further led to the phosphorylation of tyrosine kinases such as Erk1/2 and Akt, and the subsequent activation of signaling pathways within the cell [20,148]. Two additional phosphorylation sites at S294 and T294 have also been found to be important for maximal hZIP7 activity [113].…”

Section: Zinc Signaling In Cancer Cellsmentioning

confidence: 99%

Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation

Thingholm

Rönnstrand

Rosenberg

2020

Cell. Mol. Life Sci.

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Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn 2+ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.

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“…Notably, MTF-1 is the only zinc sensor protein that has been characterized in multicellular organisms (Colvin et al 2010;Choi and Bird 2014;Hardyman et al 2016). Interestingly, Taylor et al (2012) have shown that extracellular zinc results in ZIP7-dependent release of zinc from the endoplasmic reticulum, resulting in activation of multiple downstream pathways including tyrosine kinases, MAP kinases, mTOR, GSK-3, and PI3K-Akt (Nimmanon et al 2017). In this context, it is not surprising that the activated PI3K pathway converging on MTF-1 activates MTF-1, thus inducing Mt genes and other zinc homeostatic protein coding genes.…”

mentioning

confidence: 99%

The phosphoinositide 3-kinase pathway and glycogen synthase kinase-3 positively regulate the activity of metal-responsive transcription factor-1 in response to zinc ions

Andéol¹,

Bonneau

Gagné

et al. 2018

Biochem. Cell Biol.

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Metal-responsive transcription factor-1 (MTF-1) is a metal-regulatory transcription factor essential for induction of the genes encoding metallothioneins (MTs) in response to transition metal ions. Activation of MTF-1 is dependent on the interaction of zinc with the zinc fingers of the protein. In addition, phosphorylation is essential for MTF-1 transactivation. We previously showed that inhibition of phosphoinositide 3-kinase (PI3K) abrogated Mt expression and metal-induced MTF-1 activation in human hepatocellular carcinoma (HCC) HepG2 and mouse L cells, thus showing that the PI3K signaling pathway positively regulates MTF-1 activity and Mt gene expression. However, it has also been reported that inhibition of PI3K has no significant effects on Mt expression in immortalized epithelial cells and increases Mt expression in HCC cells. To further characterize the role of the PI3K pathway on the activity of MTF-1, transfection experiments were performed in HEK293 and HepG2 cells in presence of glycogen synthase kinase-3 (GSK-3), mTOR-C1, and mTOR-C2 inhibitors, as well as of siRNAs targeting Phosphatase and TENsin homolog (PTEN). We showed that inhibition of the mTOR-C2 complex inhibits the activity of MTF-1 in HepG2 and HEK293 cells, while inhibition of the mTOR-C1 complex or of PTEN stimulates MTF-1 activity in HEK293 cells. These results confirm that the PI3K pathway positively regulates MTF-1 activity. Finally, we showed that GSK-3 is required for MTF-1 activation in response to zinc ions.

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Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling

Abstract: Many important carcinogenesis-related signalling pathways are activated downstream of zinc channel ZIP7-mediated zinc store release.

Cited by 77 publications

References 41 publications

Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation

The phosphoinositide 3-kinase pathway and glycogen synthase kinase-3 positively regulate the activity of metal-responsive transcription factor-1 in response to zinc ions

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