ID S39AE_HUMAN Reviewed; 492 AA. AC Q15043; A6NH98; B4DIW3; B6EU88; D3DSR4; Q6ZME8; Q96BB3; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 07-APR-2021, entry version 156. DE RecName: Full=Metal cation symporter ZIP14 {ECO:0000305|PubMed:18270315}; DE AltName: Full=LIV-1 subfamily of ZIP zinc transporter 4 {ECO:0000303|PubMed:12659941}; DE Short=LZT-Hs4 {ECO:0000303|PubMed:12659941}; DE AltName: Full=Solute carrier family 39 member 14 {ECO:0000312|HGNC:HGNC:20858}; DE AltName: Full=Zrt- and Irt-like protein 14 {ECO:0000303|PubMed:15642354}; DE Short=ZIP-14 {ECO:0000303|PubMed:15642354}; DE Flags: Precursor; GN Name=SLC39A14 {ECO:0000312|HGNC:HGNC:20858}; GN Synonyms=KIAA0062 {ECO:0000312|EMBL:BAA06685.1}, GN ZIP14 {ECO:0000303|PubMed:15642354}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Bone marrow; RX PubMed=7584044; DOI=10.1093/dnares/1.5.223; RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N., RA Kawarabayasi Y., Ishikawa K., Tabata S.; RT "Prediction of the coding sequences of unidentified human genes. II. The RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of RT cDNA clones from human cell line KG-1."; RL DNA Res. 1:223-229(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT PRO-33. RC TISSUE=Colon; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP SUBUNIT, AND MOTIF. RX PubMed=12659941; DOI=10.1016/s0005-2736(03)00048-8; RA Taylor K.M., Nicholson R.I.; RT "The LZT proteins; the LIV-1 subfamily of zinc transporters."; RL Biochim. Biophys. Acta 1611:16-30(2003). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=15642354; DOI=10.1016/j.febslet.2004.12.006; RA Taylor K.M., Morgan H.E., Johnson A., Nicholson R.I.; RT "Structure-function analysis of a novel member of the LIV-1 subfamily of RT zinc transporters, ZIP14."; RL FEBS Lett. 579:427-432(2005). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 2). RX PubMed=18270315; DOI=10.1124/mol.107.043588; RA Girijashanker K., He L., Soleimani M., Reed J.M., Li H., Liu Z., Wang B., RA Dalton T.P., Nebert D.W.; RT "Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities RT to the ZIP8 transporter."; RL Mol. Pharmacol. 73:1413-1423(2008). RN [9] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [10] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77 AND ASN-102. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=20682781; DOI=10.1074/jbc.m110.143248; RA Zhao N., Gao J., Enns C.A., Knutson M.D.; RT "ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron RT from transferrin."; RL J. Biol. Chem. 285:32141-32150(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP FUNCTION, INDUCTION, AND TISSUE SPECIFICITY. RX PubMed=23052185; DOI=10.1007/s00011-012-0559-y; RA Sayadi A., Nguyen A.T., Bard F.A., Bard-Chapeau E.A.; RT "Zip14 expression induced by lipopolysaccharides in macrophages attenuates RT inflammatory response."; RL Inflamm. Res. 62:133-143(2013). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [15] RP INDUCTION BY IRON, UBIQUITINATION, MUTAGENESIS OF ASN-77; ASN-87 AND RP ASN-102, AND GLYCOSYLATION AT ASN-77; ASN-87 AND ASN-102. RX PubMed=24927598; DOI=10.1073/pnas.1405355111; RA Zhao N., Zhang A.S., Worthen C., Knutson M.D., Enns C.A.; RT "An iron-regulated and glycosylation-dependent proteasomal degradation RT pathway for the plasma membrane metal transporter ZIP14."; RL Proc. Natl. Acad. Sci. U.S.A. 111:9175-9180(2014). RN [16] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27703010; DOI=10.1074/jbc.m116.748632; RA Aydemir T.B., Troche C., Kim M.H., Cousins R.J.; RT "Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin RT Receptor Trafficking and Glucose Metabolism."; RL J. Biol. Chem. 291:23939-23951(2016). RN [17] RP INDUCTION. RX PubMed=28673968; DOI=10.1073/pnas.1704012114; RA Kim M.H., Aydemir T.B., Kim J., Cousins R.J.; RT "Hepatic ZIP14-mediated zinc transport is required for adaptation to RT endoplasmic reticulum stress."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E5805-E5814(2017). RN [18] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=31028174; DOI=10.1074/jbc.ra119.008762; RA Scheiber I.F., Wu Y., Morgan S.E., Zhao N.; RT "The intestinal metal transporter ZIP14 maintains systemic manganese RT homeostasis."; RL J. Biol. Chem. 294:9147-9160(2019). RN [19] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=31699897; DOI=10.1074/jbc.ra119.009371; RA Steimle B.L., Smith F.M., Kosman D.J.; RT "The solute carriers ZIP8 and ZIP14 regulate manganese accumulation in RT brain microvascular endothelial cells and control brain manganese levels."; RL J. Biol. Chem. 0:0-0(2019). RN [20] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY (ISOFORM 2), INVOLVEMENT RP IN HMNDYT2, MOTIF, VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469, AND RP CHARACTERIZATION OF VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469. RX PubMed=27231142; DOI=10.1038/ncomms11601; RA Tuschl K., Meyer E., Valdivia L.E., Zhao N., Dadswell C., Abdul-Sada A., RA Hung C.Y., Simpson M.A., Chong W.K., Jacques T.S., Woltjer R.L., Eaton S., RA Gregory A., Sanford L., Kara E., Houlden H., Cuno S.M., Prokisch H., RA Valletta L., Tiranti V., Younis R., Maher E.R., Spencer J., RA Straatman-Iwanowska A., Gissen P., Selim L.A., Pintos-Morell G., RA Coroleu-Lletget W., Mohammad S.S., Yoganathan S., Dale R.C., Thomas M., RA Rihel J., Bodamer O.A., Enns C.A., Hayflick S.J., Clayton P.T., Mills P.B., RA Kurian M.A., Wilson S.W.; RT "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood- RT onset parkinsonism-dystonia."; RL Nat. Commun. 7:11601-11601(2016). RN [21] RP INVOLVEMENT IN HCIN, VARIANT HCIN ARG-441, CHARACTERIZATION OF VARIANT HCIN RP ARG-441, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=29621230; DOI=10.1371/journal.pgen.1007321; RA Hendrickx G., Borra V.M., Steenackers E., Yorgan T.A., Hermans C., RA Boudin E., Waterval J.J., Jansen I.D.C., Aydemir T.B., Kamerling N., RA Behets G.J., Plumeyer C., D'Haese P.C., Busse B., Everts V., Lammens M., RA Mortier G., Cousins R.J., Schinke T., Stokroos R.J., Manni J.J., RA Van Hul W.; RT "Conditional mouse models support the role of SLC39A14 (ZIP14) in RT Hyperostosis Cranialis Interna and in bone homeostasis."; RL PLoS Genet. 14:E1007321-E1007321(2018). CC -!- FUNCTION: Electroneutral transporter of the plasma membrane mediating CC the cellular uptake of the divalent metal cations zinc, manganese and CC iron that are important for tissue homeostasis, metabolism, development CC and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230). CC Functions as an energy-dependent symporter, transporting through the CC membranes an electroneutral complex composed of a divalent metal cation CC and two bicarbonate anions (By similarity). Beside these endogenous CC cellular substrates, can also import cadmium a non-essential metal CC which is cytotoxic and carcinogenic (By similarity). Controls the CC cellular uptake by the intestinal epithelium of systemic zinc, which is CC in turn required to maintain tight junctions and the intestinal CC permeability (By similarity). Modifies the activity of zinc-dependent CC phosphodiesterases, thereby indirectly regulating G protein-coupled CC receptor signaling pathways important for gluconeogenesis and CC chondrocyte differentiation (By similarity). Regulates insulin receptor CC signaling, glucose uptake, glycogen synthesis and gluconeogenesis in CC hepatocytes through the zinc-dependent intracellular catabolism of CC insulin (PubMed:27703010). Through zinc cellular uptake also plays a CC role in the adaptation of cells to endoplasmic reticulum stress (By CC similarity). Major manganese transporter of the basolateral membrane of CC intestinal epithelial cells, it plays a central role in manganese CC systemic homeostasis through intestinal manganese uptake CC (PubMed:31028174). Also involved in manganese extracellular uptake by CC cells of the blood-brain barrier (PubMed:31699897). May also play a CC role in manganese and zinc homeostasis participating in their CC elimination from the blood through the hepatobiliary excretion (By CC similarity). Also functions in the extracellular uptake of free iron. CC May also function intracellularly and mediate the transport from CC endosomes to cytosol of iron endocytosed by transferrin CC (PubMed:20682781). Plays a role in innate immunity by regulating the CC expression of cytokines by activated macrophages (PubMed:23052185). CC {ECO:0000250|UniProtKB:Q75N73, ECO:0000269|PubMed:15642354, CC ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:23052185, CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:29621230, ECO:0000269|PubMed:31028174, CC ECO:0000269|PubMed:31699897}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 hydrogencarbonate(out) + Zn(2+)(out) = 2 CC hydrogencarbonate(in) + Zn(2+)(in); Xref=Rhea:RHEA:62252, CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29105; CC Evidence={ECO:0000305|PubMed:15642354}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253; CC Evidence={ECO:0000269|PubMed:15642354}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2 hydrogencarbonate(out) + Mn(2+)(out) = 2 CC hydrogencarbonate(in) + Mn(2+)(in); Xref=Rhea:RHEA:62260, CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29035; CC Evidence={ECO:0000305|PubMed:31699897}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261; CC Evidence={ECO:0000269|PubMed:31699897}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Fe(2+)(out) + 2 hydrogencarbonate(out) = Fe(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62368, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29033; Evidence={ECO:0000250|UniProtKB:Q75N73}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62369; CC Evidence={ECO:0000250|UniProtKB:Q75N73}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62256, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:48775; Evidence={ECO:0000250|UniProtKB:Q75N73}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257; CC Evidence={ECO:0000250|UniProtKB:Q75N73}; CC -!- SUBUNIT: Homotrimer. {ECO:0000269|PubMed:12659941}. CC -!- INTERACTION: CC Q15043-2; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-12176399, EBI-741037; CC Q15043-2; Q9UH03: SEPTIN3; NbExp=3; IntAct=EBI-12176399, EBI-727037; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15642354, CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:29621230}; Multi-pass membrane protein CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:31699897}; CC Multi-pass membrane protein {ECO:0000255}. Basolateral cell membrane CC {ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}; Multi-pass CC membrane protein {ECO:0000255}. Early endosome membrane CC {ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:27703010}; Multi-pass CC membrane protein {ECO:0000255}. Late endosome membrane CC {ECO:0000269|PubMed:27703010}; Multi-pass membrane protein CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:20682781}; Multi- CC pass membrane protein {ECO:0000255}. Note=Localized and functional at CC both apical and basolateral membranes of microvascular capillary CC endothelial cells that constitute the blood-brain barrier CC (PubMed:31699897). Localized at the basolateral membrane of enterocytes CC (PubMed:31028174). Enriched at the plasma membrane upon glucose uptake CC (PubMed:27703010). {ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14B CC {ECO:0000303|PubMed:18270315}; CC IsoId=Q15043-1; Sequence=Displayed; CC Name=3; CC IsoId=Q15043-2; Sequence=VSP_029728; CC Name=2 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14A CC {ECO:0000303|PubMed:18270315}; CC IsoId=Q15043-3; Sequence=VSP_040139; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with higher expression in CC liver, pancreas, fetal liver, thyroid gland, left and right ventricle, CC right atrium and fetal heart (PubMed:7584044, PubMed:15642354, CC PubMed:20682781). Weakly expressed in spleen, thymus, and peripheral CC blood leukocytes (PubMed:7584044). Expressed in liver and in brain by CC large neurons in the globus pallidus, the insular cortex and the CC dentate nucleus and to a lower extent in the putamen and the caudate CC nucleus (at protein level) (PubMed:27231142). Expressed in osteoblasts CC and giant osteoclast-like cells, but not in osteocytes found CC osteoblastoma and giant cell tumors (at protein level) CC (PubMed:29621230). Expressed by microvascular capillary endothelial CC cells that constitute the blood-brain barrier (at protein level) CC (PubMed:31699897). Expressed by macrophages (PubMed:23052185). CC {ECO:0000269|PubMed:15642354, ECO:0000269|PubMed:20682781, CC ECO:0000269|PubMed:23052185, ECO:0000269|PubMed:31699897, CC ECO:0000269|PubMed:7584044}. CC -!- TISSUE SPECIFICITY: [Isoform 2]: Widely expressed but not detected in CC brain, heart, skeletal muscle, placenta and fetal skin. CC {ECO:0000269|PubMed:27231142}. CC -!- INDUCTION: Up-regulated by iron (at protein level) (PubMed:24927598). CC Down-regulation upon iron depletion occurs through proteasomal CC degradation of the intracellular pool (PubMed:24927598). Up-regulated CC by tunicamycin, a drug inducing endoplasmic reticulum stress (at CC protein level) (PubMed:28673968). Up-regulated by CC lipopolysaccharide/LPS (PubMed:23052185). {ECO:0000269|PubMed:23052185, CC ECO:0000269|PubMed:24927598, ECO:0000269|PubMed:28673968}. CC -!- PTM: Ubiquitinated. Ubiquitination occurs upon iron depletion. The CC ubiquitinated form undergoes proteasomal degradation. CC {ECO:0000269|PubMed:24927598}. CC -!- PTM: N-glycosylated. N-glycosylation at Asn-102 is required for iron- CC regulated extraction of the transporter from membranes and subsequent CC proteasomal degradation. {ECO:0000269|PubMed:24927598}. CC -!- DISEASE: Hypermanganesemia with dystonia 2 (HMNDYT2) [MIM:617013]: A CC metabolic autosomal recessive disorder characterized by increased blood CC manganese levels, neurodegeneration, and rapidly progressive CC parkinsonism and dystonia. Affected individuals present with loss of CC developmental milestones, progressive dystonia and bulbar dysfunction CC in infancy or early childhood. Towards the end of the first decade, CC they manifest severe generalized pharmacoresistant dystonia, CC spasticity, limb contractures and scoliosis, and loss of independent CC ambulation. Cognition may be impaired, but is better preserved than CC motor function. {ECO:0000269|PubMed:27231142}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Hyperostosis cranialis interna (HCIN) [MIM:144755]: An CC autosomal dominant bone disorder characterized by endosteal CC hyperostosis and osteosclerosis of the calvaria and the skull base. The CC progressive bone overgrowth causes entrapment and dysfunction of CC cranial nerves I, II, V, VII, and VIII, its first symptoms often CC presenting during the second decade of life. CC {ECO:0000269|PubMed:29621230}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Conditional knockin mice CC overexpressing Arg-438 variant, which is the mouse equivalent of human CC variant Leu-441, in osteoblasts have a severe skeletal phenotype marked CC by a drastic increase in cortical thickness due to an enhanced CC endosteal bone formation, resembling the underlying pathology in HCI CC patients. {ECO:0000269|PubMed:29621230}. CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA06685.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D31887; BAA06685.1; ALT_INIT; mRNA. DR EMBL; AK172810; BAD18780.1; -; mRNA. DR EMBL; AK295807; BAG58625.1; -; mRNA. DR EMBL; AC087854; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC105910; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471080; EAW63681.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63682.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63683.1; -; Genomic_DNA. DR EMBL; BC015770; AAH15770.1; -; mRNA. DR CCDS; CCDS47822.1; -. [Q15043-2] DR CCDS; CCDS47823.1; -. [Q15043-1] DR CCDS; CCDS6030.1; -. [Q15043-3] DR RefSeq; NP_001121903.1; NM_001128431.2. [Q15043-1] DR RefSeq; NP_001128625.1; NM_001135153.1. [Q15043-1] DR RefSeq; NP_056174.2; NM_015359.4. [Q15043-3] DR RefSeq; XP_005273522.1; XM_005273465.2. DR RefSeq; XP_005273523.1; XM_005273466.4. [Q15043-1] DR RefSeq; XP_006716387.1; XM_006716324.2. [Q15043-1] DR RefSeq; XP_011542780.1; XM_011544478.2. [Q15043-1] DR RefSeq; XP_016868783.1; XM_017013294.1. DR RefSeq; XP_016868784.1; XM_017013295.1. DR SMR; Q15043; -. DR BioGRID; 117063; 36. DR IntAct; Q15043; 20. DR MINT; Q15043; -. DR STRING; 9606.ENSP00000352779; -. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.5.4.5; the zinc (zn(2+))-iron (fe(2+)) permease (zip) family. DR GlyGen; Q15043; 2 sites. DR iPTMnet; Q15043; -. DR PhosphoSitePlus; Q15043; -. DR SwissPalm; Q15043; -. DR BioMuta; SLC39A14; -. DR DMDM; 313104191; -. DR EPD; Q15043; -. DR jPOST; Q15043; -. DR MassIVE; Q15043; -. DR MaxQB; Q15043; -. DR PaxDb; Q15043; -. DR PeptideAtlas; Q15043; -. DR PRIDE; Q15043; -. DR ProteomicsDB; 60392; -. [Q15043-1] DR ProteomicsDB; 60393; -. [Q15043-2] DR ProteomicsDB; 60394; -. [Q15043-3] DR Antibodypedia; 9517; 184 antibodies. DR DNASU; 23516; -. DR Ensembl; ENST00000240095; ENSP00000240095; ENSG00000104635. [Q15043-2] DR Ensembl; ENST00000289952; ENSP00000289952; ENSG00000104635. [Q15043-1] DR Ensembl; ENST00000359741; ENSP00000352779; ENSG00000104635. [Q15043-3] DR Ensembl; ENST00000381237; ENSP00000370635; ENSG00000104635. [Q15043-1] DR GeneID; 23516; -. DR KEGG; hsa:23516; -. DR UCSC; uc003xbp.5; human. [Q15043-1] DR CTD; 23516; -. DR DisGeNET; 23516; -. DR GeneCards; SLC39A14; -. DR GeneReviews; SLC39A14; -. DR HGNC; HGNC:20858; SLC39A14. DR HPA; ENSG00000104635; Tissue enhanced (liver, pancreas). DR MalaCards; SLC39A14; -. DR MIM; 144755; phenotype. DR MIM; 608736; gene. DR MIM; 617013; phenotype. DR neXtProt; NX_Q15043; -. DR OpenTargets; ENSG00000104635; -. DR Orphanet; 521406; Dystonia-parkinsonism-hypermanganesemia syndrome. DR PharmGKB; PA134863701; -. DR VEuPathDB; HostDB:ENSG00000104635.13; -. DR eggNOG; KOG2693; Eukaryota. DR GeneTree; ENSGT00940000157986; -. DR InParanoid; Q15043; -. DR OMA; PCTERAF; -. DR PhylomeDB; Q15043; -. DR TreeFam; TF318470; -. DR PathwayCommons; Q15043; -. DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family. DR BioGRID-ORCS; 23516; 12 hits in 1006 CRISPR screens. DR ChiTaRS; SLC39A14; human. DR GenomeRNAi; 23516; -. DR Pharos; Q15043; Tbio. DR PRO; PR:Q15043; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q15043; protein. DR Bgee; ENSG00000104635; Expressed in right lobe of liver and 238 other tissues. DR ExpressionAtlas; Q15043; baseline and differential. DR Genevisible; Q15043; HS. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IDA:BHF-UCL. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB. DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0015296; F:anion:cation symporter activity; ISS:UniProtKB. DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; ISS:UniProtKB. DR GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IEA:Ensembl. DR GO; GO:0005381; F:iron ion transmembrane transporter activity; ISS:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0070574; P:cadmium ion transmembrane transport; ISS:UniProtKB. DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB. DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB. DR GO; GO:0006882; P:cellular zinc ion homeostasis; IDA:BHF-UCL. DR GO; GO:0002062; P:chondrocyte differentiation; ISS:UniProtKB. DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB. DR GO; GO:0098739; P:import across plasma membrane; IMP:UniProtKB. DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0033212; P:iron import into cell; IMP:UniProtKB. DR GO; GO:0034755; P:iron ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0055071; P:manganese ion homeostasis; ISS:UniProtKB. DR GO; GO:0071421; P:manganese ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; ISS:UniProtKB. DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0010817; P:regulation of hormone levels; ISS:UniProtKB. DR GO; GO:0071578; P:zinc ion import across plasma membrane; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:BHF-UCL. DR InterPro; IPR003689; ZIP. DR Pfam; PF02535; Zip; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Disease variant; Dystonia; Endosome; KW Glycoprotein; Ion transport; Lysosome; Membrane; Neurodegeneration; KW Parkinsonism; Reference proteome; Signal; Transmembrane; KW Transmembrane helix; Transport; Ubl conjugation; Zinc; Zinc transport. FT SIGNAL 1..30 FT /evidence="ECO:0000255" FT CHAIN 31..492 FT /note="Metal cation symporter ZIP14" FT /id="PRO_0000312194" FT TOPO_DOM 31..157 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 158..178 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 179..186 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 187..207 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 208..224 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 225..245 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 246..397 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 398..418 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 419..424 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 425..445 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 446..460 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 461..481 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 482..492 FT /note="Extracellular" FT /evidence="ECO:0000255" FT MOTIF 251..258 FT /note="HHHGHXHX-motif" FT /evidence="ECO:0000305|PubMed:27231142" FT MOTIF 376..381 FT /note="XEXPHE-motif" FT /evidence="ECO:0000305|PubMed:12659941" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:24927598" FT CARBOHYD 87 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24927598" FT CARBOHYD 102 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973, FT ECO:0000269|PubMed:24927598" FT VAR_SEQ 156..199 FT /note="YGLLCVTVISLCSLLGASVVPFMKKTFYKRLLLYFIALAIGTLY -> FGFL FT SVSLINLASLLGVLVLPCTEKAFFSRVLTYFIALSIGTLL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_040139" FT VAR_SEQ 445..492 FT /note="FPEMNEVCQEDERKGSILIPFIIQNLGLLTGFTIMVVLTMYSGQIQIG -> FT MEFCSVAQAGVQWCHLSSLQPLPLGLKRLSCLSLPSN (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029728" FT VARIANT 33 FT /note="L -> P (in dbSNP:rs896378)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_037450" FT VARIANT 98 FT /note="F -> V (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs879253763)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077004" FT VARIANT 383 FT /note="G -> R (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs879253766)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077005" FT VARIANT 441 FT /note="L -> R (in HCIN; loss of localization at the plasma FT membrane; loss of Zn uptake activity; dbSNP:rs1554520924)" FT /evidence="ECO:0000269|PubMed:29621230" FT /id="VAR_080794" FT VARIANT 469 FT /note="N -> K (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs750281602)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077006" FT MUTAGEN 77 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT MUTAGEN 87 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT MUTAGEN 102 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT CONFLICT 57 FT /note="L -> P (in Ref. 2; BAD18780)" FT /evidence="ECO:0000305" FT CONFLICT 314 FT /note="D -> G (in Ref. 2; BAG58625)" FT /evidence="ECO:0000305" FT CONFLICT 380 FT /note="H -> R (in Ref. 2; BAD18780)" FT /evidence="ECO:0000305" SQ SEQUENCE 492 AA; 54212 MW; F2ACE1DA4656A5F0 CRC64; MKLLLLHPAF QSCLLLTLLG LWRTTPEAHA SSLGAPAISA ASFLQDLIHR YGEGDSLTLQ QLKALLNHLD VGVGRGNVTQ HVQGHRNLST CFSSGDLFTA HNFSEQSRIG SSELQEFCPT ILQQLDSRAC TSENQENEEN EQTEEGRPSA VEVWGYGLLC VTVISLCSLL GASVVPFMKK TFYKRLLLYF IALAIGTLYS NALFQLIPEA FGFNPLEDYY VSKSAVVFGG FYLFFFTEKI LKILLKQKNE HHHGHSHYAS ESLPSKKDQE EGVMEKLQNG DLDHMIPQHC SSELDGKAPM VDEKVIVGSL SVQDLQASQS ACYWLKGVRY SDIGTLAWMI TLSDGLHNFI DGLAIGASFT VSVFQGISTS VAILCEEFPH ELGDFVILLN AGMSIQQALF FNFLSACCCY LGLAFGILAG SHFSANWIFA LAGGMFLYIS LADMFPEMNE VCQEDERKGS ILIPFIIQNL GLLTGFTIMV VLTMYSGQIQ IG //