ZIP9, a novel membrane androgen receptor and zinc transporter protein

doi:10.1016/j.ygcen.2017.04.016

General and Comparative Endocrinology

Volume 257, 1 February 2018, Pages 130-136

https://doi.org/10.1016/j.ygcen.2017.04.016 Get rights and content

Highlights

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Androgens induce rapid actions initiated at the cell surface.
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ZIP9 is a novel membrane androgen receptor first discovered in croaker ovaries.
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ZIP9 is a member of the SLC39A zinc transporter family.
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Testosterone activates G proteins and induces zinc signaling through ZIP9.
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Testosterone induces apoptosis in granulosa and cancer cells through ZIP9.

Abstract

Rapid, androgen actions initiated at the cell surface have been reported in a variety of vertebrate cells, including several macrophage and prostate cancer cell lines that lack the nuclear androgen receptor. However, until recently the identity of the novel membrane androgen receptor (mAR) mediating these nonclassical androgen actions remained unknown. In 2014, a novel mAR unrelated to nuclear androgen receptors was identified in Atlantic croaker ovaries as the zinc transporter protein, ZIP9. ZIP9 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. Zinc is a micronutrient critical for the maintenance of physiological and cellular processes, such as development, growth, protein assembly and activity, signaling, and apoptosis. Both croaker ZIP9 and human ZIP9 proteins have the binding characteristics of high affinity, specific mARs, and are coupled to G proteins. Testosterone induces apoptosis through ZIP9 in croaker granulosa cells and in human breast and prostate cancer cells by a unique mechanism involving increases in both second messengers and intracellular free zinc concentrations. ZIP9 also mediates testosterone regulation of tight junction formation in Sertoli cells and nonclassical testosterone signaling in spermatogenic cells. ZIP9 acts through several signal transduction pathways, a stimulatory G protein (Gs) in granulosa cells, an inhibitory one (Gi) in cancer cells, and a Gq11 one (Gnα11) in spermatogenic cells. ZIP9 has a very broad tissue distribution and is predicted to mediate numerous and diverse nonclassical androgen actions in vertebrates.

Introduction

Rapid, cell surface-initiated steroid actions have been reported for all major groups of steroid hormones and our understanding of membrane-mediated steroid actions has progressed rapidly over the last two decades. Membrane progestin and estrogen receptors were first cloned and characterized in 2003 and 2005, respectively (Revankar et al., 2005, Thomas et al., 2005, Zhu et al., 2003). These receptors mediate a variety of nonclassical actions in a wide range of vertebrate cells and tissues (Prossnitz and Barton, 2011, Thomas, 2012). Rapid, membrane-initiated androgen actions have also been reported in vertebrate tissues and cells, but the underlying mechanism and membrane androgen receptor (mAR) mediating many of these responses has remained elusive.

In 2014, a novel membrane androgen receptor (mAR), unrelated to the nuclear androgen receptor (nAR), was discovered in Atlantic croaker ovaries. The croaker mAR was identified as ZIP9, a member of the ZIP (SLC39A) zinc transporter family (Berg et al., 2014). Human ZIP9 expressed in nAR-negative breast and prostate cancer cell lines was also shown to display all the characteristics of a mAR (Thomas et al., 2014). Moreover, ZIP9 is the intermediary in testosterone-induced apoptosis in both croaker ovarian follicle cells and human cancer cells (Berg et al., 2014, Thomas et al., 2014). ZIP9 is the first novel protein identified in vertebrates with all the characteristics of a mAR and the only steroid receptor found to date that directly regulates zinc homeostasis by regulating zinc transport. In this short review we briefly discuss membrane-initiated androgen actions in vertebrate tissues and cells, particularly in the ovary, the discovery and characterization of ZIP9 as a mAR, the physiological functions of zinc and ZIP zinc transporters, and features of ZIP9 in other cell lines.

Section snippets

Rapid, cell surface-initiated androgen actions

Rapid androgen actions have been reported in a variety of tissues and cell types including the ovary (Braun and Thomas, 2003, Lutz et al., 2003, Machelon et al., 1998), testis (Fix et al., 2004, Lyng et al., 2000), prostate and breast cancer cell lines (Kampa et al., 2005, Lyng et al., 2000, Papadopoulou et al., 2008), and macrophages (Benten et al., 1999). Many of these responses involve G protein activation (Machelon et al., 1998, Benten et al., 1999), and while several were found to require

Identification of the croaker mAR cDNA

Testosterone (T) was observed to alter steroidogenesis through a nongenomic mechanism (not blocked by the transcription inhibitor, actinomycin D) in Atlantic croaker ovarian tissues (Braun and Thomas, 2003). This action of T was mimicked by T conjugated to BSA which indicates the action is mediated at the cell surface, and therefore suggests the presence of a mAR. Moreover, the androgen specificity of the androgen action differed from the steroid specificity of the nAR in this species, which

Zinc functions and zinc transport

Zinc is an essential metal that has many critical functions in vertebrates (Maret, 2013) and exerts pleiotropic, zinc-specific, and often cell-specific effects on morphogenesis, growth, differentiation and development (Kim et al., 2010). Zinc is an integral component of 10% (∼3000) of human proteins and is essential for their proper structure and function (Maret, 2013). Zinc acts as a catalytic cofactor for over 300 enzymes and also acts as an intracellular signaling molecule (Kochanczyk et

Localization and androgen binding characteristics of croaker ZIP9

In order to establish that ZIP9 is a mAR it is first necessary to demonstrate it is expressed on the plasma membranes of target cells and binds steroids with the characteristics of a specific membrane androgen receptor. Croaker ZIP9 mRNA and protein were found to be highly expressed in ovarian, testicular and brain tissues, with lower expression in hepatic tissues and no detectable expression in the gills. Ovarian croaker ZIP9 transcripts are abundant in the follicle cells, with only minor

G protein activation through croaker ZIP9

An essential criterion for designating a steroid binding protein as a membrane steroid receptor is to demonstrate that it can transduce steroid signals in order to elicit a cellular response. Treatment with 100 nM T caused G protein activation in croaker ZIP9-transfected cells but not in untransfected cells, as measured by increased binding of [³⁵S]-GTPγS to plasma membrane fractions. GTPγS is a nonhydrolyzable form of GTP that replaces GDP on α subunits of G proteins when they are activated. The

Regulation of intracellular free zinc levels and apoptosis through croaker ZIP9

ZIP9 would be expected to have the same zinc transport functions to increase free zinc levels in the cytoplasm as other members of the ZIP family. However, ZIP9 zinc transport activity differs from that of other ZIPs in that it is directly regulated by T in both croaker ZIP9-transfected cells and also in co-cultured G/T cells. Moreover, the zinc response to T was lost after knockdown of croaker ZIP9 expression in G/T cells, suggesting that this response solely mediated by ZIP9 (Berg et al., 2014

Hormonal regulation of ZIP9 in croaker ovaries

Ubiquitous characteristics of steroid hormones receptors, including novel membrane receptors, are that their expression and activity are hormonally regulated (Pang and Thomas, 2010, Zhu et al., 2003). ZIP9 is no exception because croaker ZIP9 expression and [³H]-T binding in ovarian tissues were shown to be upregulated 4 to 6-fold after four hours in vitro treatment with a gonadotropin (human chorionic gonadotropin, hCG). Treatments with testosterone and estradiol-17β also increase ZIP9

Characteristics of human ZIP9 in breast and prostate cancer cells

The investigation of shared characteristics of homologous novel proteins in distantly-related vertebrate groups is a powerful tool for determining their major, evolutionarily-conserved functions. The localization, steroid binding, signaling, and apoptotic functions of wildtype and recombinant human ZIP9 were investigated in nAR-null human breast cancer (MDA-MB-231 and MDA-MB-468) and prostate cancer (PC-3) cell models (Thomas et al., 2014). The results showed that human ZIP9 is expressed on the

Characteristics of ZIP9 in other cells

The results of recent studies by other research groups have supported a role of ZIP9 in nonclassical T signaling (Bulldan et al., 2016b, Shihan et al., 2015). T increases phosphorylation of ERK1/2, CREB and ATF-1 in a ZIP9-dependent manner in a nAR-null Sertoli cell line, 93RS2, resulting in increased expression of claudins that are essential constituents of tight junction formation and the maintenance of the blood-testis barrier (Bulldan et al., 2016b). Interestingly, T phosphorylates the same

Concluding remarks

The discovery that a steroid receptor mediates a cellular response through increases in intracellular zinc concentrations in addition to activation of G protein-dependent signaling, and that apoptosis is dependent upon activation of both pathways, is unprecedented. These findings reveal a previously unrecognized intimate relationship between steroid and zinc signaling. In addition, the demonstration that androgens can regulate zinc signaling through ZIP9 indicates a credible mechanism through

Conflict of interest

The authors have no conflicts of interest, financial, or otherwise.

Acknowledgment

This work was supported by the H.E.B. Endowed Chair in Marine Science (to P.T.) and University of Texas Marine Science Institute endowment-supported scholarships (to A.C).

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ReviewZIP9, a novel membrane androgen receptor and zinc transporter protein

Highlights

Abstract

Introduction

Section snippets

Rapid, cell surface-initiated androgen actions

Identification of the croaker mAR cDNA

Zinc functions and zinc transport

Localization and androgen binding characteristics of croaker ZIP9

G protein activation through croaker ZIP9

Regulation of intracellular free zinc levels and apoptosis through croaker ZIP9

Hormonal regulation of ZIP9 in croaker ovaries

Characteristics of human ZIP9 in breast and prostate cancer cells

Characteristics of ZIP9 in other cells

Concluding remarks

Conflict of interest

Acknowledgment

Genomics

Cell. Signal.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Mutat. Res.

J. Nutr. Biochem.

Exp. Cell. Res.

Adv. Nutr.

J. Trace Elem. Med. Biol.

Dev. Biol.

Biochim. Biophys. Acta

Aquat. Toxicol.

Cell. Signal.

Gen. Comp. Endocrinol.

Steroids

Mol. Cell. Endocrinol.

Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages

Mol. Biol. Cell

Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: I. Discovery in female Atlantic croaker and evidence ZIP9 mediates testosterone-induced apoptosis of ovarian follicle cells

Endocrinology

Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis

Endocrinology

Androgens inhibit estradiol-17beta synthesis in Atlantic croaker (Micropogonias undulatus) ovaries by a nongenomic mechanism initiated at the cell surface

Biol. Reprod.

Biochemical characterization of a membrane androgen receptor in the ovary of the Atlantic croaker

Biol. Reprod.

Signaling events associated with gonadotropin releasing hormone-agonisy-induced hormonal castration and its reversal in canines

Mol. Reprod. Dev.

The ubiquitous role of zinc in health and disease

J. Vet. Emerg. Crit. Care

Does 2-hydroxyflutamide inhibit apoptosis in porcine granulosa cells? – an in vitro study

J. Reprod. Dev.

The SLC39 family of metal ion transporters

Pflugers Arch

Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells

Proc. Natl. Acad. Sci. U.S.A.

Stage-specific effects of androgens and estradiol-17beta on the development of late primary and early secondary ovarian follicles of coho salmon (Oncorhynchus kisutch) in vitro

Biol. Reprod.

Review
ZIP9, a novel membrane androgen receptor and zinc transporter protein