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SLC39A7
Identifiers
Aliases	SLC39A7, D6S115E, D6S2244E, H2-KE4, HKE4, KE4, RING5, ZIP7, solute carrier family 39 member 7, AGM9
External IDs	OMIM: 601416; MGI: 95909; HomoloGene: 5072; GeneCards: SLC39A7; OMA:SLC39A7 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p21.32 Start 33,200,445 bp End 33,204,439 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 B1|17 17.98 cM Start 34,247,243 bp End 34,250,656 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium islet of Langerhans body of pancreas placenta mucosa of transverse colon Pituitary Gland anterior pituitary rectum smooth muscle tissue left adrenal gland Top expressed in islet of Langerhans adrenal gland placenta lens yolk sac Mesencephalon white adipose tissue stomach urinary bladder lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion transmembrane transporter activity protein binding zinc ion transmembrane transporter activity Cellular component integral component of membrane Golgi apparatus endoplasmic reticulum membrane endoplasmic reticulum membrane nucleoplasm Biological process metal ion transport zinc ion transmembrane transport zinc ion transport ion transport cellular zinc ion homeostasis transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7922 14977 Ensembl ENSG00000227402 ENSG00000229802 ENSG00000226614 ENSG00000112473 ENSG00000206288 ENSG00000224399 ENSMUSG00000024327 UniProt Q92504 Q31125 RefSeq (mRNA) NM_006979 NM_001077516 NM_001288777 NM_001077709 NM_008202 RefSeq (protein) NP_001070984 NP_001275706 NP_008910 NP_001070984.1 NP_008910.2 NP_001071177 NP_032228 Location (UCSC) Chr 6: 33.2 – 33.2 Mb Chr 17: 34.25 – 34.25 Mb PubMed search
Wikidata
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Zinc transporter SLC39A7 (ZIP7), also known as solute carrier family 39 member 7, is a transmembrane protein that in humans is encoded by the SLC39A7 gene. It belongs to the ZIP family, which consists of 14 proteins that transport zinc into the cytoplasm. Its primary role is to control the transport of zinc from the ER and Golgi apparatus to the cytoplasm. It also plays a role in glucose metabolism. Its structure consists of helices that bind to zinc in a binuclear metal center. Its fruit fly orthologue is Catsup.

Function

Zinc is an essential cofactor for more than 50 classes of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. Zinc cannot passively diffuse across cell membranes and requires specific transporters, such as SLC39A7, to enter the cytosol from both the extracellular environment and from intracellular storage compartments. The presence of zinc regulates the expression of ZIP transporters.

ZIP7 is a membrane transport protein of the endoplasmic reticulum. Phosphorylation of ZIP7 by casein kinase 2 stimulates the release of zinc ions from the endoplasmic reticulum This provides a signal transduction pathway by which activation of cell surface receptors such as the epidermal growth factor receptor can regulate the activity of downstream phosphatases and kinases. ZIP7 is responsible for maintaining zinc homeostasis in the ER. Due to its key role in several signaling pathways, the loss of ZIP7 results in an accumulation in the endoplasmic reticulum and cause ER stress.

ZIP7 is involved in controlling glucose metabolism in the skeletal muscle cells by affecting the insulin signaling pathway. Reduced expression in glucose metabolism genes and proteins such as Glut4, IRS1, IRS2, and Akt phosphorylation occur when ZIP7 mRNA is downregulated. When zinc released from ZIP7 binds to PTP1B, the insulin signaling pathway is activated.

Structure

There are no experimentally solved structures of ZIP7 in its entirety. ZIP7 has an predicted AlphaFold structure. ZIP7, like other ZIP proteins, has eight transmembrane (TM) helices with a binuclear metal center. Two zinc ions bind to residues on TM4 (His329, Asn330, and Asp333) and TM5 (His358, Glu395, and His362). ZIP proteins are known to make homo- or heterodimeric complexes. The specific mode of transport zinc takes through ZIP transporters has not yet been determined.

Role in Cancer

ZIP7, a member of the solute carrier family 39 (SLC39) of zinc transporters, emerges as a pivotal factor in cancer progression across multiple malignancies. In breast cancer, ZIP7 expression is markedly elevated in primary tumors, particularly in basal and Her2 subtypes, and correlates with advanced disease stage, metastasis, recurrence, and poorer prognosis. Notably, its hyperactivation is implicated in endocrine resistance, suggesting a crucial role in Endocrine therapy resistance mechanisms.

In colorectal cancer, ZIP7 upregulation is observed in tumor tissues compared to normal counterparts. Inhibition of ZIP7 leads to suppressed cell proliferation, colony formation, and enhanced apoptosis, while its heightened presence correlates with adverse patient outcomes, highlighting its significance as a potential prognostic marker. Similarly, ZIP7 exhibits elevated expression in cervical cancer tissues, where its knockdown results in inhibited proliferation, migration, and invasion of cancer cells. Furthermore, modulation of epithelial-mesenchymal transition markers underscores ZIP7's involvement in metastatic processes, suggesting its potential as a therapeutic target to impede disease progression. In hepatocellular carcinoma, specific inhibition of ZIP7 attenuates PI3K/AKT signaling, leading to suppressed cell growth, colony formation, migration, invasion, and enhanced apoptosis both in vitro and in vivo. This underscores ZIP7's critical role in hepatocellular carcinoma tumorigenesis and its potential as a therapeutic target in this malignancy.

Moreover, microRNAs play a regulatory role in ZIP7 expression across different cancer types. For instance, in prostate cancer, miR-15a-3p targets ZIP7, leading to the suppression of the Wnt/β-catenin signaling pathway and inhibition of proliferation, invasion, and epithelial-mesenchymal transition. Similarly, in gastric cancer, miR-139-5p negatively regulates ZIP7, inhibiting ZIP7-mediated activation of the Akt/mTOR pathway, thereby suppressing cell proliferation and migration while promoting apoptosis.

In a study presented at the 2024 American Association for Cancer Research (AACR) Annual Meeting, researchers introduced rabbit polyclonal antibodies specifically targeting ZIP7 to both human triple-negative breast cancer cells (TNBC) and normal breast epithelial cells (NBE) obtained from the same patient. Utilizing flow cytometry analysis, they observed substantial binding of the ZIP7 antibodies to TNBC cells, while minimal binding was noted in NBE cells from the same individual. Moreover, cytotoxicity assays revealed that the ZIP7-targeted antibodies, in combination with a secondary anti-rabbit Antibody-Drug Conjugate (ADC), selectively induced cell death in TNBC cells over NBE cells. Importantly, this preferential killing effect was attributed to the aberrant surface expression of ZIP7 on TNBC cells, coupled with its involvement in cell proliferation-related signaling pathways specific to TNBC.

In summary, ZIP7 emerges as a critical regulator of cancer progression, influencing key cellular processes such as proliferation, invasion, migration, and apoptosis across various malignancies. Targeting ZIP7 or its regulatory mechanisms holds therapeutic promise in cancer treatment strategies, highlighting its potential as a prognostic marker and therapeutic target in oncology research.

See also

• Solute carrier family

References

1. ^ ENSG00000229802, ENSG00000226614, ENSG00000112473, ENSG00000206288, ENSG00000224399 GRCh38: Ensembl release 89: ENSG00000227402, ENSG00000229802, ENSG00000226614, ENSG00000112473, ENSG00000206288, ENSG00000224399 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000024327 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ando A, Kikuti YY, Shigenari A, Kawata H, Okamoto N, Shiina T, et al. (August 1996). "cDNA cloning of the human homologues of the mouse Ke4 and Ke6 genes at the centromeric end of the human MHC region". Genomics. 35 (3): 600–602. doi:10.1006/geno.1996.0405. PMID 8812499.
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7. ^ "Entrez Gene: SLC39A7 solute carrier family 39 (zinc transporter), member 7".
8. ^ Zhao T, Huang Q, Su Y, Sun W, Huang Q, Wei W (June 2019). "Zinc and its regulators in pancreas". Inflammopharmacology. 27 (3): 453–464. doi:10.1007/s10787-019-00573-w. PMID 30756223.
9. ^ Kambe T, Matsunaga M, Takeda TA (October 2017). "Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway". International Journal of Molecular Sciences. 18 (10): 2179. doi:10.3390/ijms18102179. PMC 5666860. PMID 29048339.
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13. ^ "UniProt". www.uniprot.org. Retrieved 2024-04-13.
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19. Luo Y, Shen Y, Ju Z, Zhang Z (October 2020). "ZIP7 (SLC39A7) expression in colorectal cancer and its correlation with clinical prognosis". Translational Cancer Research. 9 (10): 6471–6478. doi:10.21037/tcr-20-2640. PMC 8798949. PMID 35117255.
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22. Cui Y, Yang Y, Ren L, Yang J, Wang B, Xing T, et al. (September 2019). "miR-15a-3p Suppresses Prostate Cancer Cell Proliferation and Invasion by Targeting SLC39A7 Via Downregulating Wnt/β-Catenin Signaling Pathway". Cancer Biotherapy & Radiopharmaceuticals. 34 (7): 472–479. doi:10.1089/cbr.2018.2722. PMID 31135177.
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Further reading

• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI (October 2003). "Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters". The Biochemical Journal. 375 (Pt 1): 51–59. doi:10.1042/BJ20030478. PMC 1223660. PMID 12839489.
• Huang L, Kirschke CP, Zhang Y, Yu YY (April 2005). "The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus". The Journal of Biological Chemistry. 280 (15): 15456–15463. doi:10.1074/jbc.M412188200. PMID 15705588.
• Kim JE, Tannenbaum SR, White FM (2005). "Global phosphoproteome of HT-29 human colon adenocarcinoma cells". Journal of Proteome Research. 4 (4): 1339–1346. doi:10.1021/pr050048h. PMID 16083285.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Genes on human chromosome 6
• Solute carrier family