ArticleThe Journal of biological chemistry2017
Dissecting the Process of Activation of Cancer-promoting Zinc-requiring Ectoenzymes by Zinc Metalation Mediated by ZNT Transporters.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Review
- Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum.Nature communications · 2026Article
- Zinc transporter ZnT5 is associated with epithelial mesenchymal transition via SMAD1 in breast cancer.International journal of experimental pathology · 2024Article
- Emerging Perspectives in Zinc Transporter Research in Prostate Cancer: An Updated Review.Nutrients · 2024Review
- Integrated pan-cancer genomic analysis reveals the role of SLC30A5 in the proliferation, metastasis, and prognosis of hepatocellular carcinoma.Journal of Cancer · 2024Article
- Metalation and activation of ZnBiophysics reviews · 2023Review
- Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.Nature communications · 2023Article
- Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins.Communications biology · 2023Article
- NovelPediatric investigation · 2023Article
- Zinc transport via ZNT5-6 and ZNT7 is critical for cell surface glycosylphosphatidylinositol-anchored protein expression.The Journal of biological chemistry · 2022Article
- Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation.The Journal of biological chemistry · 2020Article
- Zinc homeostasis in the secretory pathway in yeast.Current opinion in chemical biology · 2020Review
- Transcription factors and transporters in zinc homeostasis: lessons learned from fungi.Critical reviews in biochemistry and molecular biology · 2020Review
- Pull-Down of Metalloproteins in Their Native States by Using Desthiobiotin-Based Probes.Chembiochem : a European journal of chemical biology · 2019Article
- Zinc regulates ERp44-dependent protein quality control in the early secretory pathway.Nature communications · 2019Article
- Evaluation of the roles of the cytosolic N-terminus and His-rich loop of ZNT proteins using ZNT2 and ZNT3 chimeric mutants.Scientific reports · 2018Article
- Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models.Communications biology · 2018Article
- Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology.International journal of molecular sciences · 2017Review
- Zinc in Cellular Regulation: The Nature and Significance of "Zinc Signals".International journal of molecular sciences · 2017Review
- Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway.International journal of molecular sciences · 2017Review
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Zinc-requiring ectoenzymes, including both secreted and membrane-bound enzymes, are considered to capture zinc in their active site for their activation in the early secretory pathway. This idea has been confirmed by our studies conducted using tissue-nonspecific alkaline phosphatase (TNAP), which is elaborately activated by means of a two-step mechanism by zinc transporter 5 (ZNT5)-ZNT6 heterodimers and ZNT7 homodimers, through protein stabilization followed by enzyme activation with zinc in the early secretory pathway. However, the molecular basis of the activation process in other zinc-requiring ectoenzymes remains largely unknown. In this study, we investigated this activation process by using three cancer-promoting zinc-requiring ectoenzymes, autotaxin (ATX), matrix metalloproteinase 9 (MMP9), and carbonic anhydrase IX (CAIX), and the chicken DT40 cell mutants that we generated; we specifically focused on clarifying whether the same or a similar activation mechanism operates in these ectoenzymes. ATX activation required ZNT5-ZNT6 heterodimers and ZNT7 homodimers in a manner similar to TNAP activation, although the protein stability of ATX was differently regulated from that of TNAP. MMP9 required ZNT5-ZNT6 heterodimers and ZNT7 homodimers for its activation as well as secretion; MMP9 was not secreted into the spent medium unless both zinc-transport complexes were present. Finally, CAIX activation by zinc was mediated not only by ZNT5-ZNT6 heterodimers and ZNT7 homodimers but also by ZNT4 homodimers; thus, these three zinc-transport complexes redundantly contribute to CAIX activation. Our results provide pivotal insights into the activation processes of zinc-requiring ectoenzymes, and furthermore, they offer novel insights for potential cancer therapy applications given the cancer-promoting potencies of ATX, MMP9, and CAIX.
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