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{{Short description|Protein found in humans}}
{{Infobox gene}}
{{Infobox gene}}

'''Zinc transporter ZIP9''' also known as '''Zrt- and Irt-like protein 9''' (ZIP9) and '''solute carrier family 39 member 9''' (SLC39A9) is a [[protein]] that in humans is encoded by the ''SLC39A9'' [[gene]].<ref name="pmid28479083">{{cite journal | vauthors = Thomas P, Converse A, Berg HA | title = ZIP9, a novel membrane androgen receptor and zinc transporter protein | journal = General and Comparative Endocrinology | volume = | issue = | date = May 2017 | pmid = 28479083 | doi = 10.1016/j.ygcen.2017.04.016 }}</ref> This protein is the 9th member out of 14 ZIP family proteins, which is a [[membrane androgen receptor]] (mAR) [[G protein–coupled receptor|coupled]] to [[G protein]]s, and also classified as a [[zinc transporter protein]].<ref name="pmid28479083" /><ref name=":0">{{cite journal | vauthors = Eide DJ | title = The SLC39 family of metal ion transporters | journal = Pflugers Archiv | volume = 447 | issue = 5 | pages = 796–800 | date = February 2004 | pmid = 12748861 | doi = 10.1007/s00424-003-1074-3 }}</ref><ref name="pmid25014354">{{cite journal | vauthors = Berg AH, Rice CD, Rahman MS, Dong J, Thomas P | title = 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 | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4237–49 | date = November 2014 | pmid = 25014354 | pmc = 4197986 | doi = 10.1210/en.2014-1198 }}</ref><ref name="pmid25014355">{{cite journal | vauthors = Thomas P, Pang Y, Dong J, Berg AH | title = 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 | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4250–65 | date = November 2014 | pmid = 25014355 | pmc = 4197988 | doi = 10.1210/en.2014-1201 }}</ref> ZIP family proteins [[membrane transport protein|transport]] [[zinc ions|zinc metal]] from the [[extracellular environment]] into [[Cell (biology)|cells]] through [[cell membrane]].<ref name=":0" />
'''Zinc transporter ZIP9''', also known as '''Zrt- and Irt-like protein 9''' ('''ZIP9''') and '''solute carrier family 39 member 9''', is a [[protein]] that in humans is encoded by the ''SLC39A9'' [[gene]].<ref name="pmid28479083">{{cite journal | vauthors = Thomas P, Converse A, Berg HA | title = ZIP9, a novel membrane androgen receptor and zinc transporter protein | journal = General and Comparative Endocrinology | volume = 257| pages = 130–136 | date = May 2017 | pmid = 28479083 | doi = 10.1016/j.ygcen.2017.04.016 }}</ref> This protein is the 9th member out of 14 ZIP family proteins, which is a [[membrane androgen receptor]] (mAR) [[G protein–coupled receptor|coupled]] to [[G protein]]s, and also classified as a [[zinc transporter protein]].<ref name="pmid28479083" /><ref name=":0">{{cite journal | vauthors = Eide DJ | title = The SLC39 family of metal ion transporters | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 796–800 | date = February 2004 | pmid = 12748861 | doi = 10.1007/s00424-003-1074-3 | s2cid = 11765308 }}</ref><ref name="pmid25014354">{{cite journal | vauthors = Berg AH, Rice CD, Rahman MS, Dong J, Thomas P | title = 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 | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4237–49 | date = November 2014 | pmid = 25014354 | pmc = 4197986 | doi = 10.1210/en.2014-1198 }}</ref><ref name="pmid25014355">{{cite journal | vauthors = Thomas P, Pang Y, Dong J, Berg AH | title = 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 | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4250–65 | date = November 2014 | pmid = 25014355 | pmc = 4197988 | doi = 10.1210/en.2014-1201 }}</ref> ZIP family proteins [[membrane transport protein|transport]] [[zinc ions|zinc metal]] from the [[extracellular environment]] into [[Cell (biology)|cells]] through [[cell membrane]].<ref name=":0" />

{{TOC limit|3}}


== Classification and nomenclature ==
== Classification and nomenclature ==
Mammalian cells have two major groups of [[Zinc transporter protein|zinc transporter proteins]]; the ones that export zinc from the [[cytoplasm]] to the [[extracellular space]] ([[Efflux (microbiology)|efflux]]), which are called [[ZnT|ZnT (SLC30 family)]] , and ZIP (SLC39 family) proteins<ref name="pmid10748254">{{cite journal | vauthors = Guerinot ML | title = The ZIP family of metal transporters | journal = Biochimica Et Biophysica Acta | volume = 1465 | issue = 1-2 | pages = 190–8 | year = 2000 | pmid = 10748254 | doi = 10.1016/S0005-2736(00)00138-3 }}</ref> whose functions are in the opposite direction ([[Flux (biology)|influx]]).<ref name=":1">{{cite journal | vauthors = Lichten LA, Cousins RJ | title = Mammalian zinc transporters: nutritional and physiologic regulation | journal = Annual Review of Nutrition | volume = 29 | issue = 1 | pages = 153–76 | date = 2009-07-22 | pmid = 19400752 | doi = 10.1146/annurev-nutr-033009-083312 }}</ref> ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to [[Zinc transporter protein|Zrt]] and Irt proteins which are respectively [[zinc]] and [[iron]] -regulated [[Transport protein|transporter proteins]] in [[yeast]] and [[Arabidopsis]] that were discovered earlier than ZIP and ZnT proteins.<ref name=":1" /> ZIP family is consisted of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of [[Subfamily (biology)|subfamily I]].<ref name=":2">{{cite journal | vauthors = Matsuura W, Yamazaki T, Yamaguchi-Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T | title = SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: characterization of the ZIP subfamily I protein in vertebrate cells | journal = Bioscience, Biotechnology, and Biochemistry | volume = 73 | issue = 5 | pages = 1142–8 | date = May 2009 | pmid = 19420709 | doi = 10.1271/bbb.80910 }}</ref>
Mammalian cells have two major groups of [[zinc transporter protein]]s; the ones that export zinc from the [[cytoplasm]] to the [[extracellular space]] ([[Efflux (microbiology)|efflux]]), which are called [[ZnT|ZnT (SLC30 family)]] , and ZIP (SLC39 family) proteins<ref name="pmid10748254">{{cite journal | vauthors = Guerinot ML | title = The ZIP family of metal transporters | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1465 | issue = 1–2 | pages = 190–8 | year = 2000 | pmid = 10748254 | doi = 10.1016/S0005-2736(00)00138-3 | doi-access = }}</ref> whose functions are in the opposite direction ([[Flux (biology)|influx]]).<ref name=":1">{{cite journal | vauthors = Lichten LA, Cousins RJ | title = Mammalian zinc transporters: nutritional and physiologic regulation | journal = Annual Review of Nutrition | volume = 29 | issue = 1 | pages = 153–76 | date = 2009-07-22 | pmid = 19400752 | doi = 10.1146/annurev-nutr-033009-083312 }}</ref> ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to [[Zinc transporter protein|Zrt]] and Irt proteins which are respectively [[zinc]] and [[iron]] -regulated [[Transport protein|transporter proteins]] in [[yeast]] and [[Arabidopsis]] that were discovered earlier than ZIP and ZnT proteins.<ref name=":1" /> ZIP family consists of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of [[Subfamily (biology)|subfamily I]].<ref name=":2">{{cite journal | vauthors = Matsuura W, Yamazaki T, Yamaguchi-Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T | title = SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: characterization of the ZIP subfamily I protein in vertebrate cells | journal = Bioscience, Biotechnology, and Biochemistry | volume = 73 | issue = 5 | pages = 1142–8 | date = May 2009 | pmid = 19420709 | doi = 10.1271/bbb.80910 | s2cid = 22746139 | doi-access = free }}</ref>


== Isoforms ==
== Isoforms ==
ZIP9 can be present as 3 different [[isoforms]] in human [[cells]]. The canonical [[isoform]] of this protein has a length of 307 [[amino acids]], with a [[molecular mass]] of 32,251[[Unified atomic mass unit|Da]]. In the second isoform, amino acids 135-157 are missing, so its length and [[molecular weight]] are respectively reduced to 284 amino acids and 29,931[[Unified atomic mass unit|Da]]. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 [[Unified atomic mass unit|Da]]. Additionally, the last amino acid of isoform 3, which is usually [[serine]], is replaced with [[aspartic acid]].<ref name="UniProt_Q9NUM3">{{UniProt Full|Q9NUM3}}</ref>
ZIP9 can be present as 3 different [[isoforms]] in human [[cell (biology)|cells]]. The canonical [[isoform]] of this protein has a length of 307 [[amino acids]], with a [[molecular mass]] of 32,251[[Unified atomic mass unit|Da]]. In the second isoform, amino acids 135-157 are missing, so its length and [[molecular weight]] are respectively reduced to 284 amino acids and 29,931[[Unified atomic mass unit|Da]]. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 [[Unified atomic mass unit|Da]]. Additionally, the last amino acid of isoform 3, which is usually [[serine]], is replaced with [[aspartic acid]].<ref name="UniProt_Q9NUM3">{{UniProt Full|Q9NUM3}}</ref>
{| class="wikitable"
{| class="wikitable"
|+ZIP9 Isoforms and Sizes<ref name="UniProt_Q9NUM3" />
|+ZIP9 Isoforms and Sizes<ref name="UniProt_Q9NUM3" />
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== Discovery ==
== Discovery ==
ZIP9 [[membrane androgen receptor]] was first discovered in [[Atlantic croaker|Atlantic croaker (''Micropogonias undulatus)'']] [[brain]], [[ovary]] and [[Testicle|testicular]] [[Tissue (biology)|tissues]] and named "AR2" in 1999, together with another [[androgen receptor]] which was found only in brain tissue, and it was named "AR1" in that time.<ref>{{cite journal | vauthors = Sperry TS, Thomas P | title = Characterization of two nuclear androgen receptors in Atlantic croaker: comparison of their biochemical properties and binding specificities | journal = Endocrinology | volume = 140 | issue = 4 | pages = 1602–11 | date = April 1999 | pmid = 10098494 | doi = 10.1210/endo.140.4.6631 }}</ref> AR1 and AR2 were first thought to be [[Nuclear receptor|nuclear androgen receptors (nAR)]], however, further studies on their [[Biochemistry|biochemica]]<nowiki/>l and [[Protein function prediction|functional]] features in 2003 illustrated that they were involved in [[Non-genomic steroid hormone receptor|non-genomic mechanisms]] in the [[plasma membrane]] of the cells and were [[Membrane androgen receptor|membrane androgen receptors]].<ref name="pmid12855603">{{cite journal | vauthors = Braun AM, Thomas P | title = Androgens inhibit estradiol-17beta synthesis in Atlantic croaker (Micropogonias undulatus) ovaries by a nongenomic mechanism initiated at the cell surface | journal = Biology of Reproduction | volume = 69 | issue = 5 | pages = 1642–50 | date = November 2003 | pmid = 12855603 | doi = 10.1095/biolreprod.103.015479 }}</ref> In 2005, the similarities between the [[nucleotide]] and amino acid [[Sequence (biology)|sequences]] of AR2 and ZIP family proteins were discovered in other [[Vertebrate|vertebrates]], suggesting that AR2 is from this family of proteins.<ref name=":4" /> A study in 2014 utilised the latest research technologies to [[Molecular cloning|clone]] and [[Gene expression|express]] a particular [[Complementary DNA|cDNA]] of the female Atlantic croaker ovaries, which [[Gene expression|encoded]] a protein showing the characteristics of the canonical isoform of ZIP9, as a novel [[Membrane androgen receptor|membrane androgen receptor(mAR)]].<ref name="pmid25014354" />
ZIP9 [[membrane androgen receptor]] was first discovered in [[Atlantic croaker|Atlantic croaker (''Micropogonias undulatus)'']] [[brain]], [[ovary]] and [[Testicle|testicular]] [[Tissue (biology)|tissues]] and named "AR2" in 1999, together with another [[androgen receptor]] which was found only in brain tissue, and it was named "AR1" in that time.<ref>{{cite journal | vauthors = Sperry TS, Thomas P | title = Characterization of two nuclear androgen receptors in Atlantic croaker: comparison of their biochemical properties and binding specificities | journal = Endocrinology | volume = 140 | issue = 4 | pages = 1602–11 | date = April 1999 | pmid = 10098494 | doi = 10.1210/endo.140.4.6631 | doi-access = free }}</ref> AR1 and AR2 were first thought to be [[Nuclear receptor|nuclear androgen receptors (nAR)]], however, further studies on their [[Biochemistry|biochemical]] and [[Protein function prediction|functional]] features in 2003 illustrated that they were involved in [[Non-genomic steroid hormone receptor|non-genomic mechanisms]] in the [[plasma membrane]] of the cells and were [[membrane androgen receptor]]s.<ref name="pmid12855603">{{cite journal | vauthors = Braun AM, Thomas P | title = Androgens inhibit estradiol-17beta synthesis in Atlantic croaker (Micropogonias undulatus) ovaries by a nongenomic mechanism initiated at the cell surface | journal = Biology of Reproduction | volume = 69 | issue = 5 | pages = 1642–50 | date = November 2003 | pmid = 12855603 | doi = 10.1095/biolreprod.103.015479 | doi-access = free }}</ref> In 2005, the similarities between the [[nucleotide]] and amino acid [[Sequence (biology)|sequences]] of AR2 and ZIP family proteins were discovered in other [[vertebrate]]s, suggesting that AR2 is from this family of proteins.<ref name=":4" /> A study in 2014 utilised the latest research technologies to [[Molecular cloning|clone]] and [[Gene expression|express]] a particular [[Complementary DNA|cDNA]] of the female Atlantic croaker ovaries, which [[Gene expression|encoded]] a protein showing the characteristics of the canonical isoform of ZIP9, as a novel [[Membrane androgen receptor|membrane androgen receptor(mAR)]].<ref name="pmid25014354" />

⚫
[[File:PDB 1hzx 7TM Sketch Membrane.png|thumb|The seven-transmembrane α-helix structure of a G protein–coupled receptor, with intracellular C-terminus|274x274px|left]]

== Structure ==
== Structure ==
Unlike other ZIP subfamilies that are consisted of 8 [[Transmembrane protein|transmembrane (TM)]] [[Protein domain|domains]] with an [[Extracellular matrix|extracellular]] [[C-terminus|C-terminal]], ZIP9 is consisted of a 7 TM structure with an [[intracellular]] C-terminus.<ref name="pmid25014354" /> ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular [[Turn (biochemistry)|loop]], it contains [[histidine]]-rich clusters.<ref name="pmid25014354" /> ZIP9 and other ZIP proteins have [[Charge (chemistry)|polar]] or [[Charge (chemistry)|charged]] amino acids in their TM domains which probably play important roles in making [[Ion channel|ion transfer channels]] and therefore in importing zinc ions into cytoplasm.<ref name=":4">{{cite book|title=Zinc Finger Proteins.|vauthors=Eide DJ|publisher=Molecular Biology Intelligence Unit. Springer|year=2005|veditors=Iuchi S, Kuldell N|location=Boston, MA|chapter=The Zip Family of Zinc Transporters|doi=10.1007/0-387-27421-9_35}}</ref>
Unlike other ZIP subfamilies that are consisted of 8 [[Transmembrane protein|transmembrane (TM)]] [[Protein domain|domains]] with an [[Extracellular matrix|extracellular]] [[C-terminus|C-terminal]], ZIP9 consists of a 7 TM structure with an [[intracellular]] C-terminus.<ref name="pmid25014354" /> ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular [[Turn (biochemistry)|loop]], it contains [[histidine]]-rich clusters.<ref name="pmid25014354" /> ZIP9 and other ZIP proteins have [[Charge (chemistry)|polar]] or [[Charge (chemistry)|charged]] amino acids in their TM domains which probably play important roles in making [[Ion channel|ion transfer channels]] and therefore in importing zinc ions into cytoplasm.<ref name=":4">{{cite book|title=Zinc Finger Proteins.|pages=261–264|vauthors=Eide DJ|publisher=Molecular Biology Intelligence Unit. Springer|year=2005|veditors=Iuchi S, Kuldell N|location=Boston, MA|chapter=The Zip Family of Zinc Transporters|doi=10.1007/0-387-27421-9_35|series=Molecular Biology Intelligence Unit|isbn=978-0-306-48229-8}}</ref>
⚫
[[File:7TM4_(GPCR).png|thumb|The seven-transmembrane α-helix structure of a G protein–coupled receptor, with intracellular C-terminus|515x515px|center]]


== Location, expression and function ==
== Location, expression and function ==
[[File:Fphar-05-00033-g002.jpg|thumb|326x326px|The image illustrates the location of different zinc transporters in a cell, including ZIP9, which is located at Golgi here.<ref name="pmid24639652">{{cite journal | vauthors = Zhao L, Xia Z, Wang F | title = Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism | journal = Frontiers in Pharmacology | volume = 5 | pages = 33 | year = 2014 | pmid = 24639652 | pmc = 3944790 | doi = 10.3389/fphar.2014.00033 | doi-access = free }}</ref>]]
⚫
ZIP9 [[Flux (biology)|influxes]] [[zinc ions]] into the [[cytosol]] and its gene is [[Gene expression|expressed]] almost in every [[Tissue (biology)|tissue]] of human body. <ref name="pmid25014355" /> The [[Subcellular location|sub-cellular location]] of ZIP9 is in [[Plasma membrane|plasma]], [[Nucleus biology|nucleus]], [[endoplasmic reticulum]] and [[mitochondrial membrane]].<ref name="pmid25014355" /> One of the responsibilities of ZIP9 is the [[homeostasis]] of [[zinc]] in the [http://www.cureffi.org/2013/02/24/cell-biology-04-the-secretory-pathway/ secretory pathway], during which this protein stays within the Trans [[Golgi apparatus|Golgi]] Network regardless of the change in the [[Concentration|concentrations]] of zinc.<ref name=":2" />

[[File:Fphar-05-00033-g002.jpg|thumb|546x546px|The image illustrates the location of different zinc transporters in a cell, including ZIP9, which is located at Golgi here.<ref name="pmid24639652">{{cite journal | vauthors = Zhao L, Xia Z, Wang F | title = Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism | journal = Frontiers in Pharmacology | volume = 5 | issue = | pages = 33 | year = 2014 | pmid = 24639652 | pmc = 3944790 | doi = 10.3389/fphar.2014.00033 }}</ref>|center]]ZIP9 is the only ZIP protein that [[Cell signaling|signals]] through [[G protein]] binding, and [[pharmaceutical agents]] decrease their [[ligand binding]] once ZIP9 is [[Uncoupling protein|uncoupled]] from G proteins.<ref name="pmid28479083" /> ZIP9 is also the only member of ZIP family with [[Membrane androgen receptor|mAR]] characteristics.<ref name="pmid28479083" /> In contrast to [[Testosterone (medication)|testosterone]], which has high [[affinity (pharmacology)|affinity]] for ZIP9 with a [[Dissociation constant|K<sub>d</sub> of 14&nbsp;nM]], the other [[endogenous]] [[androgen]]s [[dihydrotestosterone]] (DHT) and [[androstenedione]] show low [[Affinity (chemistry)|affinity]] for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the [[Receptor (biochemistry)|receptor]] at sufficiently high concentrations.<ref name="pmid28479083" /> Moreover, the [[synthetic compound|synthetic]] androgens [[mibolerone]] and [[metribolone]] (R-1881), the endogenous androgen [[11-Ketotestosterone|11-ketotestoterone]], and the other [[steroid hormone]]s [[estradiol]] and [[cortisol]] are all ineffective competitors for the receptor.<ref name="pmid28479083" /> As such, [[mibolerone]] and [[metribolone]] could potentially be employed to differentiate between [[androgen receptor]]- and ZIP9-mediated responses of testosterone.<ref name="pmid28479083" />
⚫
ZIP9 [[Flux (biology)|influxes]] [[zinc ions]] into the [[cytosol]] and its gene is [[Gene expression|expressed]] almost in every [[Tissue (biology)|tissue]] of human body.<ref name="pmid25014355" /> The [[Subcellular location|sub-cellular location]] of ZIP9 is in [[Plasma membrane|plasma]], [[Nucleus biology|nucleus]], [[endoplasmic reticulum]] and [[mitochondrial membrane]].<ref name="pmid25014355" /> One of the responsibilities of ZIP9 is the [[homeostasis]] of [[zinc]] in the [http://www.cureffi.org/2013/02/24/cell-biology-04-the-secretory-pathway/ secretory pathway], during which this protein stays within the Trans [[Golgi apparatus|Golgi]] Network regardless of the change in the [[concentration]]s of zinc.<ref name=":2" />

ZIP9 is the only ZIP protein that [[Cell signaling|signals]] through [[G protein]] binding, and [[pharmaceutical agents]] decrease its [[ligand binding]] once ZIP9 is uncoupled from G proteins.<ref name="pmid28479083" /> ZIP9 is also the only member of ZIP family with [[Membrane androgen receptor|mAR]] characteristics.<ref name="pmid28479083" />

== Ligands ==

[[Testosterone]] has high [[affinity (pharmacology)|affinity]] for ZIP9 with a [[Dissociation constant|K<sub>d</sub>]] of 14&nbsp;nM and acts as an [[agonist]] of the receptor.<ref name="pmid28479083" /> In contrast, the other [[endogenous]] [[androgen]]s [[dihydrotestosterone]] (DHT) and [[androstenedione]] show low [[affinity (chemistry)|affinity]] for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the [[Receptor (biochemistry)|receptor]] at sufficiently high concentrations.<ref name="pmid28479083" /> Moreover, the [[synthetic compound|synthetic]] androgens [[mibolerone]] and [[metribolone]] (R-1881), the endogenous androgen [[11-ketotestosterone|11-ketotestoterone]], and the other [[steroid hormone]]s [[estradiol]] and [[cortisol]] are all ineffective competitors for the receptor.<ref name="pmid28479083" /> Since mibolerone and metribolone bind to and activate the nuclear [[androgen receptor]] (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone.<ref name="pmid28479083" /> The [[nonsteroidal antiandrogen]] [[bicalutamide]] has been identified as an [[receptor antagonist|antagonist]] of ZIP9.<ref name="pmid28943399">{{cite journal | vauthors = Bulldan A, Malviya VN, Upmanyu N, Konrad L, Scheiner-Bobis G | title = Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9 | journal = Biochim. Biophys. Acta | volume = 1864 | issue = 12 | pages = 2402–2414 | year = 2017 | pmid = 28943399 | doi = 10.1016/j.bbamcr.2017.09.012 | doi-access = }}</ref>


== Clinical significance ==
== Clinical significance ==


[[Zinc]] [[homeostasis]] is very important in human health, because zinc is present in the [[Protein structure|structure]] of some proteins like zinc-dependent [[metalloenzymes]] and [[Zinc finger transcription factor|zinc-finger-containing transcriptional factors]].<ref name=":3" /> In addition, zinc is involved in [[Cell signaling|signalling]] for [[cell growth]], [[Cell proliferation|proliferation]], [[Cell division|division]] and [[apoptosis]].<ref name=":3" /><ref name=":5">{{cite journal | vauthors = Li YV | title = Zinc and insulin in pancreatic beta-cells | journal = Endocrine | volume = 45 | issue = 2 | pages = 178–89 | date = March 2014 | pmid = 23979673 | doi = 10.1007/s12020-013-0032-x }}</ref> As a result, any dysfunction of [[Zinc transporter protein|zinc transporter proteins]] can be harmful for the cells, and some of them are associated with different [[cancer]]s, [[diabetes mellitus|diabetes]] and [[inflammation]].<ref name=":3">{{cite journal | vauthors = Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M | title = Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells | journal = PloS One | volume = 8 | issue = 3 | pages = e58022 | year = 2013 | pmid = 23505453 | pmc = 3591455 | doi = 10.1371/journal.pone.0058022 }}</ref> For instance, through activation of ZIP9, [[testosterone]] has been found to increase [[intracellular]] [[zinc]] levels in [[breast cancer]], [[prostate cancer]], and [[ovarian follicle]] [[cell (biology)|cell]]s and to induce [[apoptosis]] in these cells, an action which may be mediated partially or fully by increased zinc concentrations.<ref name="pmid28479083" /><ref name="pmid25325426">{{cite journal | vauthors = Pascal LE, Wang Z | title = Unzipping androgen action through ZIP9: a novel membrane androgen receptor | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4120–3 | date = November 2014 | pmid = 25325426 | doi = 10.1210/en.2014-1749 }}</ref>
[[Zinc]] [[homeostasis]] is very important in human health, because zinc is present in the [[Protein structure|structure]] of some proteins like zinc-dependent [[metalloenzymes]] and [[Zinc finger transcription factor|zinc-finger-containing transcriptional factors]].<ref name=":3" /> In addition, zinc is involved in [[Cell signaling|signalling]] for [[cell growth]], [[Cell proliferation|proliferation]], [[Cell division|division]] and [[apoptosis]].<ref name=":3" /><ref name=":5">{{cite journal | vauthors = Li YV | title = Zinc and insulin in pancreatic beta-cells | journal = Endocrine | volume = 45 | issue = 2 | pages = 178–89 | date = March 2014 | pmid = 23979673 | doi = 10.1007/s12020-013-0032-x | s2cid = 5153213 }}</ref> As a result, any dysfunction of [[zinc transporter protein]]s can be harmful for the cells, and some of them are associated with different [[cancer]]s, [[diabetes mellitus|diabetes]] and [[inflammation]].<ref name=":3">{{cite journal | vauthors = Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M | title = Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e58022 | year = 2013 | pmid = 23505453 | pmc = 3591455 | doi = 10.1371/journal.pone.0058022 | bibcode = 2013PLoSO...858022T | doi-access = free }}</ref> For instance, through activation of ZIP9, [[testosterone]] has been found to increase [[intracellular]] [[zinc]] levels in [[breast cancer]], [[prostate cancer]], and [[ovarian follicle]] [[cell (biology)|cell]]s and to induce [[apoptosis]] in these cells, an action which may be mediated partially or fully by increased zinc concentrations.<ref name="pmid28479083" /><ref name="pmid25325426">{{cite journal | vauthors = Pascal LE, Wang Z | title = Unzipping androgen action through ZIP9: a novel membrane androgen receptor | journal = Endocrinology | volume = 155 | issue = 11 | pages = 4120–3 | date = November 2014 | pmid = 25325426 | doi = 10.1210/en.2014-1749 | doi-access = free }}</ref>

===Gene mutations===
[[Mutations]] in the SLC39A9 gene can occur due to [[genetic deletion]] of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion [[mutation]] deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as [[congenital heart defects]], mild [[intellectual disability]], [[brachydactyly]], and all patients with band deletion had [[hypertelorism]] and a broad [[nasal bridge]]. Patient specific clinical issues included [[Ectopia (medicine)|ectopic]] organs, undescended testes, also called [[cryptorchidism]], and malrotation of the small intestine.
Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as [[B-cell lymphoma]] and [[B-cell chronic lymphocytic leukaemia]] (CLL).<ref name="pmid19693093">{{cite journal | vauthors= Nagel I, Bug S, Tonnies H, Ammerpohl O, Richter J, Vater I, Callet-Bauchu E, Calasanz MJ, Martinez-Climent JA, Bastard C, Salido, M | title= Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del (14)(q24. 1 q32. 33). | journal = Leukemia | volume = 23 | issue = 11 | pages = 2153–2156 | date=August 2009 | pmid=19693093 | doi=10.1038/leu.2009.149 | doi-access= free }}</ref><ref name="Nagel">{{cite web | title = Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del (14)(q24. 1 q32. 33)}}</ref>
Chimeric genes are a result of faulty [[DNA replication]], and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a [[chimeric gene]] product with a gene called PLEKHD1, that codes for an intracellular protein found within the [[cerebellum]]. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of [[schizophrenia]] and was closely related to the pathophysiology of disease.<ref name="pmid24094746">{{cite journal | vauthors= Rippey C, Walsh T, Gulsuner S, Brodsky M, Nord AS, Gasperini M, Pierce S, Spurrell C, Coe BP, Krumm N, Lee MK | title= Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. | journal = The American Journal of Human Genetics | volume = 93 | issue = 4 | pages = 697–710 | date=October 2013 | pmid=24094746 | pmc = 3791253 | doi=10.1016/j.ajhg.2013.09.004 }}</ref><ref name="Rippey">{{cite web | title = Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia.}}</ref> The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as [[Akt]] and [[Extracellular signal-regulated kinases|Erk]], leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia.<ref name="pmid24094746"/><ref name="Rippey"/>
SLC39A9 gene also forms a fusion transcript with another gene called [[MAP3K9]], that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in [[breast cancers]], demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.<ref name="pmid26227178">{{cite journal | vauthors= Kim J, Kim S, Ko S, In YH, Moon HG, Ahn SK, Kim MK, Lee M, Hwang JH, Ju YS, Kim JI | title= Recurrent fusion transcripts detected by whole‐transcriptome sequencing of 120 primary breast cancer samples. | journal = Genes, Chromosomes and Cancer| volume = 54 | issue = 11 | pages = 681–691 | date=November 2015 | pmid=26227178 | doi=10.1002/gcc.22279 | hdl= 10371/122075 | s2cid= 22740643 | hdl-access= free }}</ref><ref name="Kim">{{cite web | title = Recurrent fusion transcripts detected by whole‐transcriptome sequencing of 120 primary breast cancer samples.}}</ref>


=== Cancer ===
=== Cancer ===


==== Breast and prostate ====
==== Breast and prostate ====
A study in 2014, elucidated the intermediary role of ZIP9 in causing human [[Breast cancer|breast]] and [[prostate cancer]], as it inducted the [[apoptosis]] of testosterone in breast and prostate cancerous cells.<ref name="pmid25014355" /> unlike [[ZIP1]], [[SLC39A2|2]] and [[SLC39A3|3]], ZIP9 [[Messenger RNA|mRNA]] [[RNA expression|expression]] was increased in human prostate and breast [[Malignant Tumour|malignant]] [[biopsy]] cancer cells, which probably was because [[Cell division|cells that divide]] rapidly require more zinc. <ref name="pmid25014355" />
A study in 2014, elucidated the intermediary role of ZIP9 in causing human [[Breast cancer|breast]] and [[prostate cancer]], as it induced the [[apoptosis]] in the presence of testosterone in breast and prostate cancerous cells.<ref name="pmid25014355" /> unlike [[ZIP1]], [[SLC39A2|2]] and [[SLC39A3|3]], ZIP9 [[Messenger RNA|mRNA]] [[RNA expression|expression]] was increased in human prostate and breast [[Malignant Tumour|malignant]] [[biopsy]] cancer cells, which probably was because [[Cell division|cells that divide]] rapidly require more zinc.<ref name="pmid25014355" />


====  Brain ====
==== Brain ====
Treatment of [[Glioblastoma|glioblastoma cells]] with [[TPEN]] showed that [[upregulation]] of ZIP9 in glioblastoma cells enhances [[cell migration]] in [[brain cancer]] by influencing [[TP53|P53]] and [[GSK3B|GSK-3ß]], and also [[ERK kinase|ERK]] and [[Protein kinase B|AKT]] [[Signal transduction|signalling pathways]] in [[phosphorylation]] after [[activation]] of [[B-cell receptor|B-cell receptors]].<ref>{{cite journal | vauthors = Münnich N, Wernhart S, Hogstrand C, Schlomann U, Nimsky C, Bartsch JW | title = Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration | journal = Biometals | volume = 29 | issue = 6 | pages = 995–1004 | date = December 2016 | pmid = 27654922 | doi = 10.1007/s10534-016-9971-z }}</ref>
Treatment of [[Glioblastoma|glioblastoma cells]] with [[TPEN]] showed that [[upregulation]] of ZIP9 in glioblastoma cells enhances [[cell migration]] in [[brain cancer]] by influencing [[TP53|P53]] and [[GSK3B|GSK-3ß]], and also [[ERK kinase|ERK]] and [[Protein kinase B|AKT]] [[Signal transduction|signalling pathways]] in [[phosphorylation]] after [[activation]] of [[B-cell receptor]]s.<ref name=":3" /><ref>{{cite journal | vauthors = Münnich N, Wernhart S, Hogstrand C, Schlomann U, Nimsky C, Bartsch JW | title = Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration | journal = Biometals | volume = 29 | issue = 6 | pages = 995–1004 | date = December 2016 | pmid = 27654922 | doi = 10.1007/s10534-016-9971-z | s2cid = 20068444 }}</ref>


=== Diabetes ===
=== Diabetes ===


Zinc must be constantly supplied to [[Pancreatic β cell|Pancreatic β-cells]] to function normally and maintain [[Glycemic control|glycaemic control]].<ref name=":5" /> The [[Insulin-secreting cells|insulin secretory pathway]] in humans is highly dependent on zinc activities.<ref>{{cite journal | vauthors = Huang L | title = Zinc and its transporters, pancreatic β-cells, and insulin metabolism | journal = Vitamins and Hormones | volume = 95 | pages = 365–90 | pmid = 24559925 | doi = 10.1016/b978-0-12-800174-5.00014-4 }}</ref> The cells lose many zinc ions during the secretion of [[insulin]], and need to receive more zinc, and interestingly [[RNA expression|expression]] of ZIP9 [[Messenger RNA|mRNA]] during this process increases.<ref name=":6" /> As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for [[Therapeutic|therapeutic studies]] in the future regarding [[Diabetes, type 2|diabetes type2]]. <ref name=":6">{{cite journal | vauthors = Lawson R, Maret W, Hogstrand C | title = Expression of the ZIP/SLC39A transporters in β-cells: a systematic review and integration of multiple datasets | journal = BMC Genomics | volume = 18 | issue = 1 | pages = 719 | date = September 2017 | pmid = 28893192 | doi = 10.1186/s12864-017-4119-2 }}</ref>
Zinc must be constantly supplied to [[Pancreatic β cell|Pancreatic β-cells]] to function normally and maintain [[Glycemic control|glycaemic control]].<ref name=":5" /> The [[Insulin-secreting cells|insulin secretory pathway]] in humans is highly dependent on zinc activities.<ref>{{cite journal | vauthors = Huang L | title = Zinc and its transporters, pancreatic β-cells, and insulin metabolism | journal = Vitamins and Hormones | volume = 95 | pages = 365–90 | pmid = 24559925 | doi = 10.1016/b978-0-12-800174-5.00014-4 | year = 2014 | isbn = 9780128001745 }}</ref> The cells lose many zinc ions during the secretion of [[insulin]], and need to receive more zinc, and [[RNA expression|expression]] of ZIP9 [[Messenger RNA|mRNA]] during this process increases.<ref name=":6" /> As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for [[Therapeutic|therapeutic studies]] in the future regarding [[Diabetes, type 2|diabetes type2]].<ref name=":6">{{cite journal | vauthors = Lawson R, Maret W, Hogstrand C | title = Expression of the ZIP/SLC39A transporters in β-cells: a systematic review and integration of multiple datasets | journal = BMC Genomics | volume = 18 | issue = 1 | pages = 719 | date = September 2017 | pmid = 28893192 | doi = 10.1186/s12864-017-4119-2 | pmc = 5594519 | doi-access = free }}</ref>


== See also ==
== See also ==
Line 74: Line 93:
{{Androgen receptor modulators}}
{{Androgen receptor modulators}}


[[Category:G protein coupled receptors]]
[[Category:G protein-coupled receptors]]
[[Category:Solute carrier family]]
[[Category:Solute carrier family]]

{{gene-stub}}

Latest revision as of 10:16, 29 November 2023

SLC39A9
Identifiers
AliasesSLC39A9, ZIP-9, ZIP9, solute carrier family 39 member 9
External IDsMGI: 1914820; HomoloGene: 6935; GeneCards: SLC39A9; OMA:SLC39A9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

55334

328133

Ensembl

ENSG00000029364

ENSMUSG00000048833

UniProt

Q9NUM3

Q8BFU1

RefSeq (mRNA)

NM_026244

RefSeq (protein)

NP_080520

Location (UCSC)Chr 14: 69.4 – 69.46 MbChr 12: 80.69 – 80.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, is a protein that in humans is encoded by the SLC39A9 gene.[5] This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein.[5][6][7][8] ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane.[6]

Classification and nomenclature[edit]

Mammalian cells have two major groups of zinc transporter proteins; the ones that export zinc from the cytoplasm to the extracellular space (efflux), which are called ZnT (SLC30 family) , and ZIP (SLC39 family) proteins[9] whose functions are in the opposite direction (influx).[10] ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively zinc and iron -regulated transporter proteins in yeast and Arabidopsis that were discovered earlier than ZIP and ZnT proteins.[10] ZIP family consists of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I.[11]

Isoforms[edit]

ZIP9 can be present as 3 different isoforms in human cells. The canonical isoform of this protein has a length of 307 amino acids, with a molecular mass of 32,251Da. In the second isoform, amino acids 135-157 are missing, so its length and molecular weight are respectively reduced to 284 amino acids and 29,931Da. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 Da. Additionally, the last amino acid of isoform 3, which is usually serine, is replaced with aspartic acid.[12]

ZIP9 Isoforms and Sizes[12]
Isoform number of amino acids size (Da) transformation missing amino acids
isoform 1 307 32251 N/A N/A
isoform 2 284 29931 N/A 135-157
isoform 3 232 24626 S -----> D 233-307

Discovery[edit]

ZIP9 membrane androgen receptor was first discovered in Atlantic croaker (Micropogonias undulatus) brain, ovary and testicular tissues and named "AR2" in 1999, together with another androgen receptor which was found only in brain tissue, and it was named "AR1" in that time.[13] AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the plasma membrane of the cells and were membrane androgen receptors.[14] In 2005, the similarities between the nucleotide and amino acid sequences of AR2 and ZIP family proteins were discovered in other vertebrates, suggesting that AR2 is from this family of proteins.[15] A study in 2014 utilised the latest research technologies to clone and express a particular cDNA of the female Atlantic croaker ovaries, which encoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR).[7]

The seven-transmembrane α-helix structure of a G protein–coupled receptor, with intracellular C-terminus

Structure[edit]

Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an extracellular C-terminal, ZIP9 consists of a 7 TM structure with an intracellular C-terminus.[7] ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains histidine-rich clusters.[7] ZIP9 and other ZIP proteins have polar or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm.[15]

Location, expression and function[edit]

The image illustrates the location of different zinc transporters in a cell, including ZIP9, which is located at Golgi here.[16]

ZIP9 influxes zinc ions into the cytosol and its gene is expressed almost in every tissue of human body.[8] The sub-cellular location of ZIP9 is in plasma, nucleus, endoplasmic reticulum and mitochondrial membrane.[8] One of the responsibilities of ZIP9 is the homeostasis of zinc in the secretory pathway, during which this protein stays within the Trans Golgi Network regardless of the change in the concentrations of zinc.[11]

ZIP9 is the only ZIP protein that signals through G protein binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins.[5] ZIP9 is also the only member of ZIP family with mAR characteristics.[5]

Ligands[edit]

Testosterone has high affinity for ZIP9 with a Kd of 14 nM and acts as an agonist of the receptor.[5] In contrast, the other endogenous androgens dihydrotestosterone (DHT) and androstenedione show low affinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the receptor at sufficiently high concentrations.[5] Moreover, the synthetic androgens mibolerone and metribolone (R-1881), the endogenous androgen 11-ketotestoterone, and the other steroid hormones estradiol and cortisol are all ineffective competitors for the receptor.[5] Since mibolerone and metribolone bind to and activate the nuclear androgen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone.[5] The nonsteroidal antiandrogen bicalutamide has been identified as an antagonist of ZIP9.[17]

Clinical significance[edit]

Zinc homeostasis is very important in human health, because zinc is present in the structure of some proteins like zinc-dependent metalloenzymes and zinc-finger-containing transcriptional factors.[18] In addition, zinc is involved in signalling for cell growth, proliferation, division and apoptosis.[18][19] As a result, any dysfunction of zinc transporter proteins can be harmful for the cells, and some of them are associated with different cancers, diabetes and inflammation.[18] For instance, through activation of ZIP9, testosterone has been found to increase intracellular zinc levels in breast cancer, prostate cancer, and ovarian follicle cells and to induce apoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations.[5][20]

Gene mutations[edit]

Mutations in the SLC39A9 gene can occur due to genetic deletion of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion mutation deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as congenital heart defects, mild intellectual disability, brachydactyly, and all patients with band deletion had hypertelorism and a broad nasal bridge. Patient specific clinical issues included ectopic organs, undescended testes, also called cryptorchidism, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as B-cell lymphoma and B-cell chronic lymphocytic leukaemia (CLL).[21][22] Chimeric genes are a result of faulty DNA replication, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a chimeric gene product with a gene called PLEKHD1, that codes for an intracellular protein found within the cerebellum. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of schizophrenia and was closely related to the pathophysiology of disease.[23][24] The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as Akt and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia.[23][24] SLC39A9 gene also forms a fusion transcript with another gene called MAP3K9, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.[25][26]

Cancer[edit]

Breast and prostate[edit]

A study in 2014, elucidated the intermediary role of ZIP9 in causing human breast and prostate cancer, as it induced the apoptosis in the presence of testosterone in breast and prostate cancerous cells.[8] unlike ZIP1, 2 and 3, ZIP9 mRNA expression was increased in human prostate and breast malignant biopsy cancer cells, which probably was because cells that divide rapidly require more zinc.[8]

Brain[edit]

Treatment of glioblastoma cells with TPEN showed that upregulation of ZIP9 in glioblastoma cells enhances cell migration in brain cancer by influencing P53 and GSK-3ß, and also ERK and AKT signalling pathways in phosphorylation after activation of B-cell receptors.[18][27]

Diabetes[edit]

Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control.[19] The insulin secretory pathway in humans is highly dependent on zinc activities.[28] The cells lose many zinc ions during the secretion of insulin, and need to receive more zinc, and expression of ZIP9 mRNA during this process increases.[29] As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.[29]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000029364 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048833 – 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. ^ a b c d e f g h i Thomas P, Converse A, Berg HA (May 2017). "ZIP9, a novel membrane androgen receptor and zinc transporter protein". General and Comparative Endocrinology. 257: 130–136. doi:10.1016/j.ygcen.2017.04.016. PMID 28479083.
  6. ^ a b Eide DJ (February 2004). "The SLC39 family of metal ion transporters". Pflügers Archiv. 447 (5): 796–800. doi:10.1007/s00424-003-1074-3. PMID 12748861. S2CID 11765308.
  7. ^ a b c d Berg AH, Rice CD, Rahman MS, Dong J, Thomas P (November 2014). "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. 155 (11): 4237–49. doi:10.1210/en.2014-1198. PMC 4197986. PMID 25014354.
  8. ^ a b c d e Thomas P, Pang Y, Dong J, Berg AH (November 2014). "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. 155 (11): 4250–65. doi:10.1210/en.2014-1201. PMC 4197988. PMID 25014355.
  9. ^ Guerinot ML (2000). "The ZIP family of metal transporters". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1465 (1–2): 190–8. doi:10.1016/S0005-2736(00)00138-3. PMID 10748254.
  10. ^ a b Lichten LA, Cousins RJ (2009-07-22). "Mammalian zinc transporters: nutritional and physiologic regulation". Annual Review of Nutrition. 29 (1): 153–76. doi:10.1146/annurev-nutr-033009-083312. PMID 19400752.
  11. ^ a b Matsuura W, Yamazaki T, Yamaguchi-Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T (May 2009). "SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: characterization of the ZIP subfamily I protein in vertebrate cells". Bioscience, Biotechnology, and Biochemistry. 73 (5): 1142–8. doi:10.1271/bbb.80910. PMID 19420709. S2CID 22746139.
  12. ^ a b Universal protein resource accession number Q9NUM3 at UniProt.
  13. ^ Sperry TS, Thomas P (April 1999). "Characterization of two nuclear androgen receptors in Atlantic croaker: comparison of their biochemical properties and binding specificities". Endocrinology. 140 (4): 1602–11. doi:10.1210/endo.140.4.6631. PMID 10098494.
  14. ^ Braun AM, Thomas P (November 2003). "Androgens inhibit estradiol-17beta synthesis in Atlantic croaker (Micropogonias undulatus) ovaries by a nongenomic mechanism initiated at the cell surface". Biology of Reproduction. 69 (5): 1642–50. doi:10.1095/biolreprod.103.015479. PMID 12855603.
  15. ^ a b Eide DJ (2005). "The Zip Family of Zinc Transporters". In Iuchi S, Kuldell N (eds.). Zinc Finger Proteins. Molecular Biology Intelligence Unit. Boston, MA: Molecular Biology Intelligence Unit. Springer. pp. 261–264. doi:10.1007/0-387-27421-9_35. ISBN 978-0-306-48229-8.
  16. ^ Zhao L, Xia Z, Wang F (2014). "Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism". Frontiers in Pharmacology. 5: 33. doi:10.3389/fphar.2014.00033. PMC 3944790. PMID 24639652.
  17. ^ Bulldan A, Malviya VN, Upmanyu N, Konrad L, Scheiner-Bobis G (2017). "Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9". Biochim. Biophys. Acta. 1864 (12): 2402–2414. doi:10.1016/j.bbamcr.2017.09.012. PMID 28943399.
  18. ^ a b c d Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M (2013). "Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells". PLOS ONE. 8 (3): e58022. Bibcode:2013PLoSO...858022T. doi:10.1371/journal.pone.0058022. PMC 3591455. PMID 23505453.
  19. ^ a b Li YV (March 2014). "Zinc and insulin in pancreatic beta-cells". Endocrine. 45 (2): 178–89. doi:10.1007/s12020-013-0032-x. PMID 23979673. S2CID 5153213.
  20. ^ Pascal LE, Wang Z (November 2014). "Unzipping androgen action through ZIP9: a novel membrane androgen receptor". Endocrinology. 155 (11): 4120–3. doi:10.1210/en.2014-1749. PMID 25325426.
  21. ^ Nagel I, Bug S, Tonnies H, Ammerpohl O, Richter J, Vater I, Callet-Bauchu E, Calasanz MJ, Martinez-Climent JA, Bastard C, Salido, M (August 2009). "Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del (14)(q24. 1 q32. 33)". Leukemia. 23 (11): 2153–2156. doi:10.1038/leu.2009.149. PMID 19693093.
  22. ^ "Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del (14)(q24. 1 q32. 33)". {{cite web}}: Missing or empty |url= (help)
  23. ^ a b Rippey C, Walsh T, Gulsuner S, Brodsky M, Nord AS, Gasperini M, Pierce S, Spurrell C, Coe BP, Krumm N, Lee MK (October 2013). "Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia". The American Journal of Human Genetics. 93 (4): 697–710. doi:10.1016/j.ajhg.2013.09.004. PMC 3791253. PMID 24094746.
  24. ^ a b "Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia". {{cite web}}: Missing or empty |url= (help)
  25. ^ Kim J, Kim S, Ko S, In YH, Moon HG, Ahn SK, Kim MK, Lee M, Hwang JH, Ju YS, Kim JI (November 2015). "Recurrent fusion transcripts detected by whole‐transcriptome sequencing of 120 primary breast cancer samples". Genes, Chromosomes and Cancer. 54 (11): 681–691. doi:10.1002/gcc.22279. hdl:10371/122075. PMID 26227178. S2CID 22740643.
  26. ^ "Recurrent fusion transcripts detected by whole‐transcriptome sequencing of 120 primary breast cancer samples". {{cite web}}: Missing or empty |url= (help)
  27. ^ Münnich N, Wernhart S, Hogstrand C, Schlomann U, Nimsky C, Bartsch JW (December 2016). "Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration". Biometals. 29 (6): 995–1004. doi:10.1007/s10534-016-9971-z. PMID 27654922. S2CID 20068444.
  28. ^ Huang L (2014). "Zinc and its transporters, pancreatic β-cells, and insulin metabolism". Vitamins and Hormones. 95: 365–90. doi:10.1016/b978-0-12-800174-5.00014-4. ISBN 9780128001745. PMID 24559925.
  29. ^ a b Lawson R, Maret W, Hogstrand C (September 2017). "Expression of the ZIP/SLC39A transporters in β-cells: a systematic review and integration of multiple datasets". BMC Genomics. 18 (1): 719. doi:10.1186/s12864-017-4119-2. PMC 5594519. PMID 28893192.
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