SLC39A4 Membrane Protein Introduction

Introduction of SLC39A4

Zinc transporter ZIP4 (short for ZIP-4), alternatively called the Zrt- and Irt-like protein 4 or SLC39A4, is encoded by the SLC39A4 gene in human. The zinc transporter SLC39A4 belongs to the ZIP family, which is also known as solute carrier family 39 (SLC39) that transport Zn²⁺ across the membrane into the cytosol, either from the lumen of intracellular organelles or from the extracellular space. Zinc transporter SLC39A4 is highly expressed in kidney, stomach, colon, small intestine, duodenum, and jejunum.

Function of SLC39A4 Membrane Protein

Zrt- and Irt-like protein (ZIP) family has been proved to control the cytosolic concentration of zinc by transporting zinc into the cytoplasm from the extracellular space or from intracellular compartments. Since human zinc transporter SLC39A4 is expressed in the gastrointestinal tract on the apical surface of enterocytes, it is thought to be the major zinc transporter responsible for the uptake of dietary zinc. SLC39A4 plays a crucial role in cellular zinc homeostasis as a zinc transporter and is regulated in response to zinc availability. It is involved in maintaining the cellular zinc level by uptaking dietary zinc into intestinal epithelial cells and releasing zinc from vesicular compartments. And, mutations in the SLC39A4 gene, which encoded SLC39A4 protein, are considered to be the cause of a genetic disorder of zinc-deficiency acrodermatitis enteropathica (AE). Notably, SLC39A4 levels are distinctly higher in human pancreatic cancer. A previous study has shown a significant outcome of aberrant SLC39A4 expression in contributing to pancreatic cancer pathogenesis and progression, and thus indicate a therapeutic strategy whereby SLC39A4 is targeted to inhibit pancreatic cancer growth.

Fig.1 Model structure of the TMD of hSLC39A4. (Zhang, 2017)

Application of SLC39A4 Membrane Protein in Literature

1. Jin H., et al. Exosomal zinc transporter ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer. Cancer Sci. 2018, 109(9): 2946-2956. PubMed ID: 30007115
   
   

   Authors of this study identify exosomal ZIP4 as a new diagnostic biomarker for pancreatic cancer since it is proved to promote cancer growth.

2. Gartmann L., et al. Expression of zinc transporters ZIP4, ZIP14 and ZnT9 in hepatic carcinogenesis-An immunohistochemical study. J Trace Elem Med Biol. 2018, 49: 35-42. PubMed ID: 29895370
   
   

   Authors of this study reveal a regulatory/functional link between the zinc-homeostasis and the development/progression of HCC, which is worth to be further investigated.

3. Liu M., et al. ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism. Clin Cancer Res. 2018, 24(13): 3186-3196. PubMed ID: 29615456
   
   

   This study aims to investigate the underlying mechanism and define a new signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis, and the results indicate ZIP4 can be considered as a novel therapeutic target for pancreatic cancer.

4. Fan Q., et al. The novel ZIP4 regulation and its role in ovarian cancer. Oncotarget. 2017, 8(52): 90090-90107. PubMed ID: 29163813
   
   

   Authors of this study reveal that ZIP4 is a novel and important cancer stem cell regulator in ovarian cancer.

5. Hardy A.B., et al. Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells. PLoS One. 2015, 10(3): e0119136. PubMed ID: 25806541
   
   

   This article aims to define the zinc transport role of Zip4 in beta cells, and the results find that Zip4 mediates increases in cytoplasmic and granular zinc pools and stimulates glucose-dependent insulin secretion in vitro.

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Reference

1. Zhang T, et al. (2017). Crystal structures of a ZIP zinc transporter reveal a binuclear metal center in the transport pathway. Science advances. 3(8), p.e1700344.

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