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Zinc transporter SLC39A7

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SLC39A7
Identifiers
AliasesSLC39A7, D6S115E, D6S2244E, H2-KE4, HKE4, KE4, RING5, ZIP7, solute carrier family 39 member 7, AGM9
External IDsOMIM: 601416; MGI: 95909; HomoloGene: 5072; GeneCards: SLC39A7; OMA:SLC39A7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7922

14977

Ensembl

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 MbChr 17: 34.25 – 34.25 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6][7][8][9][10][11] It belongs to the ZIP family, which consists of 14 proteins that transport zinc into the cytoplasm.[8][9][10][11] Its primary role is to control the transport of zinc from the ER and Golgi apparatus to the cytoplasm.[8][9][10][11] It also plays a role in glucose metabolism.[8][10][12] Its structure consists of helices that bind to zinc in a binuclear metal center.[9][10] Its fruit fly orthologue is Catsup.

ZIP7 3D Alpha Fold structure modeled in ChimeraX. Accession number: AF-Q92504-F1[13]

Function

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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.[7] The presence of zinc regulates the expression of ZIP transporters.[8]

ZIP7 is a membrane transport protein of the endoplasmic reticulum.[14] Phosphorylation of ZIP7 by casein kinase 2 stimulates the release of zinc ions from the endoplasmic reticulum[15] 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.[9] 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.[8][9][11]

ZIP7 is involved in controlling glucose metabolism in the skeletal muscle cells by affecting the insulin signaling pathway.[8][10][12] Reduced expression in glucose metabolism genes and proteins such as Glut4, IRS1, IRS2, and Akt phosphorylation occur when ZIP7 mRNA is downregulated.[8][12] When zinc released from ZIP7 binds to PTP1B, the insulin signaling pathway is activated.[12]

Structure

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Zoomed in ZIP7 3D Alpha Fold structure modeled in ChimeraX. No zinc atom is present. The dark blue helix is TM4 and the orange helix is TM5. The red residues are amino acids involved in binding to two zinc atoms.[10] Accession number: AF-Q92504-F1[13]

There are no experimentally solved structures of ZIP7 in its entirety.[13] ZIP7 has an predicted AlphaFold structure.[13] ZIP7, like other ZIP proteins, has eight transmembrane (TM) helices with a binuclear metal center.[9][10] Two zinc ions bind to residues on TM4 (His329, Asn330, and Asp333) and TM5 (His358, Glu395, and His362).[9][10][13] ZIP proteins are known to make homo- or heterodimeric complexes.[9] The specific mode of transport zinc takes through ZIP transporters has not yet been determined.[9]

Role in Cancer

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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.[16][17]

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.[18][19] 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.[20] 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.[21]

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.[22][23]

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.[24]

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

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References

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  1. ^ a b c ENSG00000229802, ENSG00000226614, ENSG00000112473, ENSG00000206288, ENSG00000224399 GRCh38: Ensembl release 89: ENSG00000227402, ENSG00000229802, ENSG00000226614, ENSG00000112473, ENSG00000206288, ENSG00000224399 – Ensembl, May 2017
  2. ^ a b c 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.
  6. ^ Hanson IM, Trowsdale J (Aug 1991). "Colinearity of novel genes in the class II regions of the MHC in mouse and human". Immunogenetics. 34 (1): 5–11. doi:10.1007/BF00212306. PMID 1855816. S2CID 30046348.
  7. ^ a b "Entrez Gene: SLC39A7 solute carrier family 39 (zinc transporter), member 7".
  8. ^ a b c d e f g h 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. ^ a b c d e f g h i j 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.
  10. ^ a b c d e f g h i Zhang T, Liu J, Fellner M, Zhang C, Sui D, Hu J (August 2017). "Crystal structures of a ZIP zinc transporter reveal a binuclear metal center in the transport pathway". Science Advances. 3 (8): e1700344. Bibcode:2017SciA....3E0344Z. doi:10.1126/sciadv.1700344. PMC 5573306. PMID 28875161.
  11. ^ a b c d Baltaci AK, Yuce K (March 2018). "Zinc Transporter Proteins". Neurochemical Research. 43 (3): 517–530. doi:10.1007/s11064-017-2454-y. PMID 29243032.
  12. ^ a b c d Fukunaka A, Fujitani Y (February 2018). "Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity". International Journal of Molecular Sciences. 19 (2): 476. doi:10.3390/ijms19020476. PMC 5855698. PMID 29415457.
  13. ^ a b c d e "UniProt". www.uniprot.org. Retrieved 2024-04-13.
  14. ^ Taylor KM, Morgan HE, Johnson A, Nicholson RI (January 2004). "Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters". The Biochemical Journal. 377 (Pt 1): 131–139. doi:10.1042/BJ20031183. PMC 1223853. PMID 14525538.
  15. ^ Taylor KM, Kille P, Hogstrand C (May 2012). "Protein kinase CK2 opens the gate for zinc signaling". Cell Cycle. 11 (10): 1863–1864. doi:10.4161/cc.20414. PMC 3359116. PMID 22580452.
  16. ^ Liu L, Yang J, Wang C (August 2020). "Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer". Bioscience Reports. 40 (8). doi:10.1042/BSR20200764. PMC 7426635. PMID 32744318.
  17. ^ Jones S, Farr G, Nimmanon T, Ziliotto S, Gee JM, Taylor KM (April 2022). "The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer". Exploration of Targeted Anti-Tumor Therapy. 3 (2): 224–239. doi:10.37349/etat.2022.00080. PMC 7612740. PMID 35591900.
  18. ^ Sheng N, Yan L, You W, Tan G, Gong J, Chen H, et al. (October 2017). "Knockdown of SLC39A7 inhibits cell growth and induces apoptosis in human colorectal cancer cells". Acta Biochimica et Biophysica Sinica. 49 (10): 926–934. doi:10.1093/abbs/gmx094. PMID 28981607.
  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.
  20. ^ Wei Y, Dong J, Li F, Wei Z, Tian Y (2017). "Knockdown of SLC39A7 suppresses cell proliferation, migration and invasion in cervical cancer". EXCLI Journal. 16: 1165–1176. doi:10.17179/excli2017-690. PMID 29285013.
  21. ^ Tong Q, Yan D, Cao Y, Dong X, Abula Y, Yang H, et al. (July 2023). "NVS-ZP7-4 inhibits hepatocellular carcinoma tumorigenesis and promotes apoptosis via PI3K/AKT signaling". Scientific Reports. 13 (1): 11795. Bibcode:2023NatSR..1311795T. doi:10.1038/s41598-023-38596-7. PMC 10362011. PMID 37479837.
  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.
  23. ^ Zhang Y, Bai J, Si W, Yuan S, Li Y, Chen X (February 2020). "SLC39A7, regulated by miR-139-5p, induces cell proliferation, migration and inhibits apoptosis in gastric cancer via Akt/mTOR signaling pathway". Bioscience Reports. 40 (2). doi:10.1042/BSR20200041. PMC 7048674. PMID 32109290.
  24. ^ Manavalan JS, Mor D, Davis J, Saini S, Pal I, Feith D, et al. (22 March 2024). "Abstract 4109: Discovery of a novel cancer-specific antigen for therapeutic targeting using the Oncotope platform". Cancer Research. 84 (6_Supplement): 4109. doi:10.1158/1538-7445.AM2024-4109.

Further reading

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

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