Opinion
Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation

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Zinc, which is essential for many cellular processes, is controlled by zinc transporters and through buffering by metallothioneins and glutathione. Although zinc is increasingly implicated in disease states, little is known about how zinc regulates cellular biochemical pathways. Recent seminal articles have revealed discrete zinc-trafficking pathways that are linked to signalling cascades, particularly those involving protein phosphatase inhibition and downstream activation of mitogen-activated protein kinases and tyrosine kinases. Here, we discuss the mechanisms of cellular zinc homeostasis, and we propose an important role for the zinc transporter solute carrier family 39, member 7 (SLC39A7; commonly referred to as ZIP7). ZIP7 releases zinc from the endoplasmic reticulum and might be required for tyrosine kinase activation. These observations position ZIP7 at a critical node in zinc-mediated tyrosine kinase signalling and suggest that this protein might form a novel target for diseases such as cancer where prevention of tyrosine kinase activation would be therapeutically advantageous.

Section snippets

The roles of zinc in biology and disease

Zinc is essential for normal cell growth and development and is involved in protein, nucleic acid, carbohydrate and lipid metabolism, as well as in the control of gene transcription, growth and differentiation [1]. There are in excess of 2300 genes in the human genome (Ensemble release 49) with the Gene Ontology annotation ‘zinc ion binding’, and in many of these genes, zinc has a structural role in generating zinc fingers for DNA binding. Although much of the zinc in a cell is associated with

Zinc transporters

Zinc is unable to passively traverse cell membranes, and intracellular zinc homeostasis is largely regulated by two families of genes whose protein products traffic zinc across membranes. The ZnT family (previously termed the cation diffusion facilitator [CDF] family and now termed SLC30A) of zinc transporters efflux zinc from cells [23], whereas the ZIP family (now termed SLC39A) of zinc transporters [24] influx zinc into cells. The ZnT family contains nine human sequences (reviewed in Ref.

Cellular zinc trafficking and dynamics

A model for zinc trafficking within cells has been proposed by Colvin et al.[46] using computational modelling of experimental data obtained from cultured cortical neurones challenged with added zinc in the medium. Of the three models that were tested for ability to match intracellular free zinc transients and total zinc content, only one model was able to reproduce the experimental results with accuracy. This successful model predicted that zinc entering the cell was associated in the

The intracellular zinc wave and the activation of cell signalling elements

Observations that changes in the cytosolic concentration of labile Zn2+ are used to regulate cellular processes have recently led to the concept of Zn2+ as an intracellular signalling substance. This was first demonstrated with metal-regulatory transcription factor 1 (MTF1), which changes the transcription rates of numerous genes in response to a rise in cytoplasmic Zn2+ concentration 47, 48, 49, but more recently this concept has been applied to early, non-genomic events. It was recently shown

The molecular and cellular topology of ZIP7

Members of the ZIP family of zinc transporters are predicted to contain eight TM domains with extracellular N and C termini and a long variable region in the cytoplasmic loop between TM3 and TM4 [24] (Figure 2a). The variable loop contains a histidine-rich repeat with the general formula (HX)n (where H equals histidine, X equals another amino acid and n equals 3 to 6) and is thought to be responsible for metal ion transport [24]. The ZIP family of zinc transporters is divided into four

ZIP7-mediated zinc release is essential for tyrosine kinase activation

Our group has begun to define a previously unidentified role for zinc in contributing to oestrogen-receptor-dependent and -independent forms of endocrine-resistant breast cancer through its capacity to sustain the activity of growth-factor signalling. As stated above, elevated concentrations of labile Zn2+ have been shown to cause inactivation of several protein phosphatases in vivo and in vitro. Some of these phosphatases are involved in the dephosphorylation and inactivation of EGFR, HER2,

ZIP7: a gatekeeper for intracellular zinc release?

Several pieces of recent data are suggestive of a mechanism for zinc distribution in cells that is represented in Figure 3. Essentially, extracellular zinc entering the cell is immediately buffered within the as yet undefined ‘zinc muffler’ and translocated into an intracellular zinc store, such as the ER [46]. The zinc is then released back into the cytosol from the ER through the action of ZIP7. This part of the model has already been substantiated by the demonstrated ability of ZIP7 siRNA to

Therapeutic implications

It is proposed that ZIP7-mediated release of zinc and the resulting Zn2+ wave is responsible for the inhibition of phosphatases that has been previously attributed to zinc 7, 9, 11, 53. If true, this mechanism has considerable implications for the treatment of diseases, such as cancer, that often exhibit aberrant activation of many different tyrosine kinases and provides ZIP7 as a new target for inhibiting tyrosine kinase activation. The added benefit of targeting ZIP7 in diseases such as

Concluding remarks

The true significance of zinc in cell function is only now emerging. It is not only an essential ion with a role in numerous cellular systems, it can also act as a second messenger, extending its role to one that is comparable to calcium [3]. The idea of zinc as an intracellular signalling molecule has been discussed for many years [63], but the experimental evidence for this was generally dismissed as effects caused by zinc deficiency or toxicity. Although the role of zinc in transcriptional

Disclosure statement

The authors have no conflict of interest to declare.

Acknowledgements

We acknowledge financial support from Tenovus the cancer charity and the Breast Cancer Campaign.

Glossary

Epidermal growth factor receptor (EGFR)
EGFR is the cell-surface receptor for members of the epidermal growth factor family (EGF family) of ligands of which there are four members; EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). EGFR is activated by ligand binding, resulting in the formation of homo- or heterodimers with other family members which stimulates its protein-tyrosine kinase activity. This activation results in initiation of several signal transduction cascades,

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