| SLC39A9 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SLC39A9, ZIP-9, ZIP9, solute carrier family 39 member 9 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | MGI:1914820;HomoloGene:6935;GeneCards:SLC39A9;OMA:SLC39A9 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Zinc transporter ZIP9, also known asZrt- and Irt-like protein 9 (ZIP9) andsolute carrier family 39 member 9, is aprotein that in humans is encoded by theSLC39A9gene.[5] This protein is the ninth member out of 14 ZIP family proteins, and is amembrane androgen receptor (mAR)coupled toG proteins that is classified as azinc transporter protein.[5][6][7][8] ZIP family proteinstransportzinc metal from theextracellular environment intocells throughcell membrane.[6]
Mammalian cells have two major groups ofzinc transporter proteins; the ones that export zinc from thecytoplasm to theextracellular space (efflux), which are calledZnT (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 toZrt and Irt proteins which are respectivelyzinc andiron -regulatedtransporter proteins inyeast andArabidopsis 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 ofsubfamily I.[11]
ZIP9 can be present as three differentisoforms in humancells. The canonicalisoform of this protein has a length of 307amino acids, with amolecular mass of32251 Da. In the second isoform, amino acids 135–157 are missing, so its length andmolecular weight are respectively reduced to 284 amino acids and29931 Da. In the third isoform the amino acids 233–307 are missing, so the isoform only has 232 amino acids and its molecular mass is24626 Da. Additionally, the last amino acid of isoform 3, which is usuallyserine, is replaced withaspartic acid.[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 |
ZIP9membrane androgen receptor was first discovered inAtlantic croaker (Micropogonias undulatus)brain,ovary andtesticulartissues and named "AR2" in 1999, together with anotherandrogen receptor which was found only in brain tissue, and it was named "AR1" in that time.[13] AR1 and AR2 were first thought to benuclear androgen receptors (nAR), however, further studies on theirbiochemical andfunctional features in 2003 illustrated that they were involved innon-genomic mechanisms in theplasma membrane of the cells and weremembrane androgen receptors.[14] In 2005, the similarities between thenucleotide and amino acidsequences of AR2 and ZIP family proteins were discovered in othervertebrates, suggesting that AR2 is from this family of proteins.[15] A study in 2014 utilised the latest research technologies toclone andexpress a particularcDNA of the female Atlantic croaker ovaries, whichencoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novelmembrane androgen receptor(mAR).[7]
Unlike other ZIP subfamilies that are consisted of 8transmembrane (TM)domains with anextracellularC-terminal, ZIP9 consists of a 7 TM structure with anintracellular 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 intracellularloop, it containshistidine-rich clusters.[7] ZIP9 and other ZIP proteins havepolar orcharged amino acids in their TM domains which probably play important roles in makingion transfer channels and therefore in importing zinc ions into cytoplasm.[15]
ZIP9influxeszinc ions into thecytosol and its gene isexpressed almost in everytissue of human body.[8] Thesub-cellular location of ZIP9 is inplasma,nucleus,endoplasmic reticulum andmitochondrial membrane.[8] One of the responsibilities of ZIP9 is thehomeostasis ofzinc in thesecretory pathway, during which this protein stays within the TransGolgi Network regardless of the change in theconcentrations of zinc.[11]
ZIP9 is the only ZIP protein thatsignals throughG protein binding, andpharmaceutical agents decrease itsligand binding once ZIP9 is uncoupled from G proteins.[5] ZIP9 is also the only member of ZIP family withmAR characteristics.[5]
Testosterone has highaffinity for ZIP9 with aKd of 14 nM and acts as anagonist of the receptor.[5] In contrast, the otherendogenousandrogensdihydrotestosterone (DHT) andandrostenedione show lowaffinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating thereceptor at sufficiently high concentrations.[5] Moreover, thesynthetic androgensmibolerone andmetribolone (R-1881), the endogenous androgen11-ketotestoterone, and the othersteroid hormonesestradiol andcortisol are all ineffective competitors for the receptor.[5] Since mibolerone and metribolone bind to and activate the nuclearandrogen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone.[5] Thenonsteroidal antiandrogenbicalutamide has been identified as anantagonist of ZIP9.[17]
Zinchomeostasis is very important in human health, because zinc is present in thestructure of some proteins like zinc-dependentmetalloenzymes andzinc-finger-containing transcriptional factors.[18] In addition, zinc is involved insignalling forcell growth,proliferation,division andapoptosis.[18][19] As a result, any dysfunction ofzinc transporter proteins can be harmful for the cells, and some of them are associated with differentcancers,diabetes andinflammation.[18] For instance, through activation of ZIP9,testosterone has been found to increaseintracellularzinc levels inbreast cancer,prostate cancer, andovarian folliclecells and to induceapoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations.[5][20]
Mutations in the SLC39A9 gene can occur due togenetic deletion of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletionmutation 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 ascongenital heart defects, mildintellectual disability,brachydactyly, and all patients with band deletion hadhypertelorism and a broadnasal bridge. Patient specific clinical issues includedectopic organs, undescended testes, also calledcryptorchidism, 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 asB-cell lymphoma andB-cell chronic lymphocytic leukaemia (CLL).[21][22]Chimeric genes are a result of faultyDNA 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 achimeric gene product with a gene called PLEKHD1, that codes for an intracellular protein found within thecerebellum. 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 ofschizophrenia 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 asAkt andErk, 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 calledMAP3K9, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence inbreast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.[25][26]
A study in 2014, elucidated the intermediary role of ZIP9 in causing humanbreast andprostate cancer, as it induced theapoptosis in the presence of testosterone in breast and prostate cancerous cells.[8] unlikeZIP1,2 and3, ZIP9mRNAexpression was increased in human prostate and breastmalignantbiopsy cancer cells, which probably was becausecells that divide rapidly require more zinc.[8]
Treatment ofglioblastoma cells withTPEN showed thatupregulation of ZIP9 in glioblastoma cells enhancescell migration inbrain cancer by influencingP53 andGSK-3ß, and alsoERK andAKTsignalling pathways inphosphorylation afteractivation ofB-cell receptors.[18][27]
Zinc must be constantly supplied toPancreatic β-cells to function normally and maintainglycaemic control.[19] Theinsulin secretory pathway in humans is highly dependent on zinc activities.[28] The cells lose many zinc ions during the secretion ofinsulin, and need to receive more zinc, andexpression of ZIP9mRNA during this process increases.[29] As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target fortherapeutic studies in the future regardingdiabetes type2.[29]
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