SLC39A9 Membrane Protein Introduction

Introduction of SLC39A9

Zinc transporter ZIP9 (SLC39A9) is one of the 14 members of the ZIP (ZRT-and Irt-like Protein, SLC39A) family that regulates zinc homeostasis by transporting zinc across cell and organelle membranes into the cytoplasm. Besides, SLC39A9 is also identified as a novel membrane androgen receptor. It is coupled to different G proteins for signaling transduction, such as the Gs protein in granulosa cells, Gi protein in cancer cells, and Gnα11 in spermatogenic cells. SLC39A9 is widely expressed in different human tissues. Structurally, human SLC39A9 protein is predicted to have 8 transmembrane domains with extracellular C termini.

Functions of SLC39A9 Membrane Protein

As SLC39A9 is a membrane androgen receptor and a zinc transporter, it functions by binding to androgen and can mediate zinc homeostasis. Upon binding to testosterone, apoptosis can be induced via SLC39A9 protein in croaker granulosa and human cancer cells (breast and prostate cancer cells). Besides, SLC39A9 is up-regulated in malignant breast and prostate tissues, suggesting that it is a potential therapeutic target for treating breast and prostate cancers. Moreover, SLC39A9 also mediates testosterone regulation of tight junction formation in Sertoli cells and non-classical testosterone signaling in spermatogenic cells.

Application of SLC39A9 Membrane Protein in Literature

1. Thomas P., et al. Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: II. Role of human ZIP9 in testosterone-induced prostate and breast cancer cell apoptosis. Endocrinology. 2014, 155(11): 4250-4265. PubMed ID: 25014355
   
   

   Using triple-negative human breast cancer MDA-MB-468 cells that expressed moderate levels of ZIP9 and nAR-negative PC-3 human prostate cells that expressed lower levels of ZIP9, this study investigated whether human ZIP9 functioned as a membrane androgen receptor. The results showed that in both cell types, human ZIP9 functioned as an mAR and zinc transporter, and mediated testosterone-induced apoptosis via MAPK- and zinc-dependent pathways.

2. Shihan M., et al. Non-classical testosterone signaling in spermatogenic GC-2 cells is mediated through ZIP9 interacting with Gnα11. Cellular Signaling. 2015, 27(10): 2077-2086. PubMed ID: 26208885
   
   

   This study reported that in the spermatogenic cell line GC-2, the non-classical signaling pathway of testosterone was mediated by the ZIP9 zinc transporter.

3. Bulldan A., et al. Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017, 1864(12): 2402-2414. PubMed ID: 28943399
   
   

   Using a cell line that lacked the classical androgen receptor, this study showed that ZIP9-mediated phosphorylation of Erk1/2, CREB, or ATF-1, as well as expression of claudin-5 and zonula occludens-1 by testosterone, can be completely antagonized by bicalutamide, which was an anti-androgen of significant clinical impact.

4. Converse A., et al. Membrane androgen receptor ZIP9 induces croaker ovarian cell apoptosis via stimulatory G protein alpha subunit and MAP kinase signaling. Endocrinology. 2017, 158(9): 3015-3029. PubMed ID: 28633436
   
   

   This study investigated the underlying mechanisms of ZIP9 in the croaker ovarian cell apoptosis. The results showed that ZIP9 induced apoptosis of croaker ovarian cells via stimulatory G protein α subunit and MAP kinase signaling.

5. Ondricek K. and Thomas P. Effects of hypoxia exposure on apoptosis and expression of membrane steroid receptors, ZIP9, mPRα, and GPER in Atlantic croaker ovaries. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology. 2018. PubMed ID: 30025815
   
   

   The effects of chronic hypoxia exposure of female Atlantic croaker on oogenesis and apoptosis of ovarian follicles as well as the ovarian expression and functions of the membrane steroid receptors, ZIP9, mPRα, and GPER were investigated.

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