S39AE_MOUSE
ID S39AE_MOUSE Reviewed; 489 AA.
AC Q75N73; A0A0R4J1V1; Q80U85; Q8VDL0;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Metal cation symporter ZIP14 {ECO:0000305|PubMed:18270315};
DE AltName: Full=Factor for adipocyte differentiation 123 {ECO:0000312|EMBL:BAD16742.1};
DE Short=FAD-123 {ECO:0000312|EMBL:BAD16742.1};
DE AltName: Full=Solute carrier family 39 member 14 {ECO:0000312|MGI:MGI:2384851};
DE AltName: Full=Zrt- and Irt-like protein 14 {ECO:0000303|PubMed:15863613};
DE Short=ZIP-14 {ECO:0000303|PubMed:15863613};
DE Flags: Precursor;
GN Name=Slc39a14 {ECO:0000312|MGI:MGI:2384851};
GN Synonyms=Fad123 {ECO:0000312|EMBL:BAD16742.1},
GN Kiaa0062 {ECO:0000312|EMBL:BAC65479.2},
GN Zip14 {ECO:0000303|PubMed:15863613};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=15794747; DOI=10.1111/j.1742-4658.2005.04580.x;
RA Tominaga K., Kagata T., Johmura Y., Hishida T., Nishizuka M., Imagawa M.;
RT "SLC39A14, a LZT protein, is induced in adipogenesis and transports zinc.";
RL FEBS J. 272:1590-1599(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-489 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=12693553; DOI=10.1093/dnares/10.1.35;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S.,
RA Nakajima D., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: II.
RT The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:35-48(2003).
RN [5]
RP FUNCTION, TRANSPORTER ACTIVITY, INDUCTION BY IL6, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=15863613; DOI=10.1073/pnas.0502257102;
RA Liuzzi J.P., Lichten L.A., Rivera S., Blanchard R.K., Aydemir T.B.,
RA Knutson M.D., Ganz T., Cousins R.J.;
RT "Interleukin-6 regulates the zinc transporter Zip14 in liver and
RT contributes to the hypozincemia of the acute-phase response.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:6843-6848(2005).
RN [6]
RP FUNCTION, TRANSPORTER ACTIVITY, INDUCTION BY IL6, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=16950869; DOI=10.1073/pnas.0606424103;
RA Liuzzi J.P., Aydemir F., Nam H., Knutson M.D., Cousins R.J.;
RT "Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:13612-13617(2006).
RN [7]
RP INDUCTION BY IL6, TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=17065364; DOI=10.1124/jpet.106.112912;
RA Kobayashi K., Kuroda J., Shibata N., Hasegawa T., Seko Y., Satoh M.,
RA Tohyama C., Takano H., Imura N., Sakabe K., Fujishiro H., Himeno S.;
RT "Induction of metallothionein by manganese is completely dependent on
RT interleukin-6 production.";
RL J. Pharmacol. Exp. Ther. 320:721-727(2007).
RN [8]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBSTRATE SPECIFICITY (ISOFORMS 1 AND 2),
RP BIOPHYSICOCHEMICAL PROPERTIES (ISOFORMS 1 AND 2), ACTIVITY REGULATION,
RP ALTERNATIVE SPLICING(ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY (ISOFORMS 1 AND 2), AND GLYCOSYLATION.
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 FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=19179618; DOI=10.1152/ajpgi.90676.2008;
RA Lichten L.A., Liuzzi J.P., Cousins R.J.;
RT "Interleukin-1beta contributes via nitric oxide to the upregulation and
RT functional activity of the zinc transporter Zip14 (Slc39a14) in murine
RT hepatocytes.";
RL Am. J. Physiol. 296:G860-G867(2009).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-52 AND ASN-100.
RC TISSUE=Myoblast;
RX PubMed=19656770; DOI=10.1074/mcp.m900195-mcp200;
RA Gundry R.L., Raginski K., Tarasova Y., Tchernyshyov I., Bausch-Fluck D.,
RA Elliott S.T., Boheler K.R., Van Eyk J.E., Wollscheid B.;
RT "The mouse C2C12 myoblast cell surface N-linked glycoproteome:
RT identification, glycosite occupancy, and membrane orientation.";
RL Mol. Cell. Proteomics 8:2555-2569(2009).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-52; ASN-75; ASN-85 AND ASN-100.
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 [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [13]
RP FUNCTION.
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 [14]
RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=21653899; DOI=10.1152/ajpcell.00479.2010;
RA Pinilla-Tenas J.J., Sparkman B.K., Shawki A., Illing A.C., Mitchell C.J.,
RA Zhao N., Liuzzi J.P., Cousins R.J., Knutson M.D., Mackenzie B.;
RT "Zip14 is a complex broad-scope metal-ion transporter whose functional
RT properties support roles in the cellular uptake of zinc and nontransferrin-
RT bound iron.";
RL Am. J. Physiol. 301:C862-C871(2011).
RN [15]
RP FUNCTION, TISSUE SPECIFICITY, GLYCOSYLATION, AND DISRUPTION PHENOTYPE.
RX PubMed=21445361; DOI=10.1371/journal.pone.0018059;
RA Hojyo S., Fukada T., Shimoda S., Ohashi W., Bin B.H., Koseki H., Hirano T.;
RT "The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-
RT mediated signaling required for systemic growth.";
RL PLoS ONE 6:E18059-E18059(2011).
RN [16]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23110240; DOI=10.1371/journal.pone.0048679;
RA Aydemir T.B., Chang S.M., Guthrie G.J., Maki A.B., Ryu M.S., Karabiyik A.,
RA Cousins R.J.;
RT "Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose
RT homeostasis during the innate immune response (endotoxemia).";
RL PLoS ONE 7:E48679-E48679(2012).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=25428902; DOI=10.1152/ajpgi.00021.2014;
RA Guthrie G.J., Aydemir T.B., Troche C., Martin A.B., Chang S.M.,
RA Cousins R.J.;
RT "Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier
RT function.";
RL Am. J. Physiol. 308:G171-G178(2015).
RN [18]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26028554; DOI=10.1016/j.cmet.2015.05.002;
RA Jenkitkasemwong S., Wang C.Y., Coffey R., Zhang W., Chan A., Biel T.,
RA Kim J.S., Hojyo S., Fukada T., Knutson M.D.;
RT "SLC39A14 Is Required for the Development of Hepatocellular Iron Overload
RT in Murine Models of Hereditary Hemochromatosis.";
RL Cell Metab. 22:138-150(2015).
RN [19]
RP FUNCTION, INDUCTION, AND DISRUPTION PHENOTYPE.
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 [20]
RP INDUCTION.
RX PubMed=28057442; DOI=10.1016/j.exer.2016.12.008;
RA Sterling J., Guttha S., Song Y., Song D., Hadziahmetovic M., Dunaief J.L.;
RT "Iron importers Zip8 and Zip14 are expressed in retina and regulated by
RT retinal iron levels.";
RL Exp. Eye Res. 155:15-23(2017).
RN [21]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=28536273; DOI=10.1523/jneurosci.0285-17.2017;
RA Aydemir T.B., Kim M.H., Kim J., Colon-Perez L.M., Banan G., Mareci T.H.,
RA Febo M., Cousins R.J.;
RT "Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese
RT Deposition and Produces Neurotoxic Signatures and Diminished Motor
RT Activity.";
RL J. Neurosci. 37:5996-6006(2017).
RN [22]
RP FUNCTION, AND 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 [23]
RP DISRUPTION PHENOTYPE.
RX PubMed=29632817; DOI=10.1002/2211-5463.12399;
RA Sasaki S., Tsukamoto M., Saito M., Hojyo S., Fukada T., Takami M.,
RA Furuichi T.;
RT "Disruption of the mouse Slc39a14 gene encoding zinc transporter ZIP14 is
RT associated with decreased bone mass, likely caused by enhanced bone
RT resorption.";
RL FEBS Open Bio 8:655-663(2018).
RN [24]
RP DEVELOPMENTAL STAGE, AND MUTAGENESIS OF LEU-438.
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).
RN [25]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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).
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:15863613, PubMed:16950869, PubMed:18270315,
CC PubMed:19179618, PubMed:21653899, PubMed:28673968). Functions as an
CC energy-dependent symporter, transporting through the membranes an
CC electroneutral complex composed of a divalent metal cation and two
CC bicarbonate anions (PubMed:18270315). Beside these endogenous cellular
CC substrates, can also import cadmium a non-essential metal which is
CC cytotoxic and carcinogenic (PubMed:18270315). Controls the cellular
CC uptake by the intestinal epithelium of systemic zinc, which is in turn
CC required to maintain tight junctions and the intestinal permeability
CC (PubMed:25428902). 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 (PubMed:21445361). Regulates insulin
CC receptor signaling, glucose uptake, glycogen synthesis and
CC gluconeogenesis in hepatocytes through the zinc-dependent intracellular
CC catabolism of insulin (PubMed:27703010). Through zinc cellular uptake
CC also plays a role in the adaptation of cells to endoplasmic reticulum
CC stress (PubMed:28673968). Major manganese transporter of the
CC basolateral membrane of intestinal epithelial cells, it plays a central
CC role in manganese systemic homeostasis through intestinal manganese
CC uptake (PubMed:31028174). Also involved in manganese extracellular
CC uptake by cells of the blood-brain barrier (By similarity). May also
CC play a role in manganese and zinc homeostasis participating in their
CC elimination from the blood through the hepatobiliary excretion
CC (PubMed:28536273). Also functions in the extracellular uptake of free
CC iron (PubMed:16950869, PubMed:19179618, PubMed:21653899,
CC PubMed:23110240, PubMed:26028554). May also function intracellularly
CC and mediate the transport from endosomes to cytosol of iron endocytosed
CC by transferrin (PubMed:20682781). Plays a role in innate immunity by
CC regulating the expression of cytokines by activated macrophages (By
CC similarity). {ECO:0000250|UniProtKB:Q15043,
CC ECO:0000269|PubMed:15863613, ECO:0000269|PubMed:16950869,
CC ECO:0000269|PubMed:18270315, ECO:0000269|PubMed:19179618,
CC ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:21445361,
CC ECO:0000269|PubMed:21653899, ECO:0000269|PubMed:23110240,
CC ECO:0000269|PubMed:25428902, ECO:0000269|PubMed:26028554,
CC ECO:0000269|PubMed:27703010, ECO:0000269|PubMed:28536273,
CC ECO:0000269|PubMed:28673968, ECO:0000269|PubMed:31028174}.
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:21653899};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253;
CC Evidence={ECO:0000269|PubMed:15863613, ECO:0000269|PubMed:16950869,
CC ECO:0000269|PubMed:18270315, ECO:0000269|PubMed:21653899};
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:18270315, ECO:0000305|PubMed:21653899};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261;
CC Evidence={ECO:0000269|PubMed:18270315, ECO:0000269|PubMed:21653899};
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:0000269|PubMed:16950869,
CC ECO:0000269|PubMed:21653899};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62369;
CC Evidence={ECO:0000269|PubMed:16950869, ECO:0000269|PubMed:21653899};
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:0000269|PubMed:18270315};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257;
CC Evidence={ECO:0000269|PubMed:18270315};
CC -!- ACTIVITY REGULATION: Inhibited by cyanide and therefore dependent of an
CC energy source (PubMed:18270315). Inhibited by DIDS/4,4'-
CC diisothiocyanatostilbene-2,2'-disulfonic acid, an inhibitor
CC hydrogencarbonate-dependent transporters (PubMed:18270315).
CC {ECO:0000269|PubMed:18270315}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:18270315};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius.
CC {ECO:0000269|PubMed:18270315};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]:
CC Kinetic parameters:
CC KM=0.14 mM for Cd(2+) {ECO:0000269|PubMed:18270315};
CC KM=4.4 mM for Mn(2+) {ECO:0000269|PubMed:18270315};
CC KM=2.3 uM for Fe(2+) {ECO:0000269|PubMed:21653899};
CC KM=1.9 uM for Zn(2+) {ECO:0000269|PubMed:21653899};
CC Vmax=25 pmol/min/mg enzyme for the transport of Cd(2+)
CC {ECO:0000269|PubMed:18270315};
CC Vmax=330 pmol/min/mg enzyme for the transport of Mn(2+)
CC {ECO:0000269|PubMed:18270315};
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:18270315,
CC ECO:0000269|PubMed:21653899};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius.
CC {ECO:0000269|PubMed:18270315};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 2]:
CC Kinetic parameters:
CC KM=1.1 mM for Cd(2+) {ECO:0000269|PubMed:18270315};
CC KM=18.2 mM for Mn(2+) {ECO:0000269|PubMed:18270315};
CC Vmax=113 pmol/min/mg enzyme for the transport of Cd(2+)
CC {ECO:0000269|PubMed:18270315};
CC Vmax=1140 pmol/min/mg enzyme for the transport of Mn(2+)
CC {ECO:0000269|PubMed:18270315};
CC pH dependence:
CC Optimum pH is 7.5 (PubMed:18270315). Optimum temperature is 37
CC degrees Celsius (PubMed:18270315). {ECO:0000269|PubMed:18270315};
CC -!- SUBUNIT: Homotrimer. {ECO:0000250|UniProtKB:Q15043}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15794747,
CC ECO:0000269|PubMed:15863613, ECO:0000269|PubMed:16950869,
CC ECO:0000269|PubMed:19179618}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:18270315};
CC Multi-pass membrane protein {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000269|PubMed:25428902, ECO:0000269|PubMed:28536273}; Multi-pass
CC membrane protein {ECO:0000255}. Early endosome membrane
CC {ECO:0000250|UniProtKB:Q15043}; Multi-pass membrane protein
CC {ECO:0000255}. Late endosome membrane {ECO:0000250|UniProtKB:Q15043};
CC Multi-pass membrane protein {ECO:0000255}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q15043}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Localized at the basolateral membrane of
CC enterocytes (PubMed:25428902, PubMed:28536273). Enriched at the plasma
CC membrane upon glucose uptake (By similarity). Localized and functional
CC at both apical and basolateral membranes of microvascular capillary
CC endothelial cells that constitute the blood-brain barrier (By
CC similarity). {ECO:0000250|UniProtKB:Q15043,
CC ECO:0000269|PubMed:25428902, ECO:0000269|PubMed:28536273}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=ZIP14B {ECO:0000303|PubMed:18270315};
CC IsoId=Q75N73-1; Sequence=Displayed;
CC Name=2; Synonyms=ZIP14A {ECO:0000303|PubMed:18270315};
CC IsoId=Q75N73-3; Sequence=VSP_060552;
CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:18270315). Highly and
CC transiently expressed during the early stage of adipocyte
CC differentiation. Strongly expressed in liver, preadipocyte, duodenum
CC and jejunum, moderately in brain, heart, skeletal muscle, spleen,
CC pancreas, kidney and white adipose cells. Expression is almost
CC undetectable in lung, testis and brown adipose cells (PubMed:15794747,
CC PubMed:15863613, PubMed:16950869, PubMed:17065364, PubMed:25428902).
CC Expressed by chondrocytes and pituitary cells (PubMed:21445361).
CC {ECO:0000269|PubMed:15794747, ECO:0000269|PubMed:15863613,
CC ECO:0000269|PubMed:16950869, ECO:0000269|PubMed:17065364,
CC ECO:0000269|PubMed:18270315, ECO:0000269|PubMed:21445361,
CC ECO:0000269|PubMed:25428902}.
CC -!- TISSUE SPECIFICITY: [Isoform 1]: More strongly expressed in brain.
CC {ECO:0000269|PubMed:18270315}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: More strongly expressed in liver,
CC kidney and duodenum. {ECO:0000269|PubMed:18270315}.
CC -!- DEVELOPMENTAL STAGE: In the KS483 cell model for osteoblast
CC differentiation, expression levels peaks during the mineralization
CC phase (days 18-21 of differentiation). {ECO:0000269|PubMed:29621230}.
CC -!- INDUCTION: Up-regulated during the lipopolysaccharide/LPS-induced
CC inflammatory response (at protein level) (PubMed:16950869). Up-
CC regulated by IL6 (PubMed:15863613, PubMed:16950869, PubMed:17065364).
CC Up-regulated by interleukin-1/IL1 via nitric oxide (PubMed:19179618).
CC Up-regulated upon endoplasmic reticulum stress induced by tunicamycin
CC or high-fat diet (at protein level) (PubMed:28673968). Up-regulated
CC into hepatocytes upon glucose uptake (at protein level)
CC (PubMed:27703010). Up-regulated by iron in retina (at protein level)
CC (PubMed:28057442). {ECO:0000269|PubMed:15863613,
CC ECO:0000269|PubMed:16950869, ECO:0000269|PubMed:17065364,
CC ECO:0000269|PubMed:19179618, ECO:0000269|PubMed:27703010,
CC ECO:0000269|PubMed:28057442, ECO:0000269|PubMed:28673968}.
CC -!- PTM: Ubiquitinated. Ubiquitination occurs upon iron depletion. The
CC ubiquitinated form undergoes proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q15043}.
CC -!- PTM: N-glycosylated (PubMed:18270315, PubMed:21445361). N-glycosylation
CC at Asn-100 is required for iron-regulated extraction of the transporter
CC from membranes and subsequent proteasomal degradation (By similarity).
CC {ECO:0000250|UniProtKB:Q15043, ECO:0000269|PubMed:18270315,
CC ECO:0000269|PubMed:21445361}.
CC -!- DISRUPTION PHENOTYPE: Homozygous knockout mice exhibit growth
CC retardation and dwarfism, visible even in neonates (PubMed:21445361).
CC They exhibit moderate osteoporotic phenotypes associated with decreased
CC bone volume and trabecular number, and increased trabecular separation
CC (PubMed:21445361). The length of the long bones is also significantly
CC reduced (PubMed:21445361). The decrease in bone mass is associated with
CC increased bone resorption (PubMed:29632817). The metabolism of these
CC mice is also affected and they constitute a model of metabolic
CC endotoxemia with high body fat, hypoglycemia and hyperinsulinemia
CC (PubMed:23110240, PubMed:27703010). The knockout of the gene also
CC results in less effective blood manganese elimination and accumulation
CC in the brain where it alters motor functions (PubMed:28536273).
CC Knockout mice also display increased iron absorption and decreased
CC lipopolysaccharide/LPS-induced IL-6 production (PubMed:23110240,
CC PubMed:26028554). The permeability of the intestinal barrier is also
CC compromised (PubMed:25428902). Conditional intestinal-specific knockout
CC of the gene results in increased manganese levels in brain and liver
CC while the liver-specific knockout reduces manganese levels only in
CC liver (PubMed:31028174). {ECO:0000269|PubMed:21445361,
CC ECO:0000269|PubMed:23110240, ECO:0000269|PubMed:25428902,
CC ECO:0000269|PubMed:26028554, ECO:0000269|PubMed:27703010,
CC ECO:0000269|PubMed:28536273, ECO:0000269|PubMed:29632817,
CC ECO:0000269|PubMed:31028174}.
CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION: [Isoform 1]:
CC Sequence=BAC65479.2; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};
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DR EMBL; AB177995; BAD16742.1; -; mRNA.
DR EMBL; AC025669; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC021530; AAH21530.1; -; mRNA.
DR EMBL; AK122197; BAC65479.2; ALT_SEQ; Transcribed_RNA.
DR CCDS; CCDS36969.1; -. [Q75N73-1]
DR CCDS; CCDS49536.1; -. [Q75N73-3]
DR RefSeq; NP_001128623.1; NM_001135151.1. [Q75N73-3]
DR RefSeq; NP_001128624.1; NM_001135152.1. [Q75N73-3]
DR RefSeq; NP_659057.2; NM_144808.4. [Q75N73-1]
DR RefSeq; XP_006518851.1; XM_006518788.3. [Q75N73-3]
DR RefSeq; XP_006518852.1; XM_006518789.3. [Q75N73-3]
DR AlphaFoldDB; Q75N73; -.
DR SMR; Q75N73; -.
DR BioGRID; 229393; 3.
DR STRING; 10090.ENSMUSP00000066108; -.
DR GlyConnect; 2832; 1 N-Linked glycan (1 site).
DR GlyGen; Q75N73; 4 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q75N73; -.
DR PhosphoSitePlus; Q75N73; -.
DR SwissPalm; Q75N73; -.
DR EPD; Q75N73; -.
DR jPOST; Q75N73; -.
DR MaxQB; Q75N73; -.
DR PaxDb; Q75N73; -.
DR PeptideAtlas; Q75N73; -.
DR PRIDE; Q75N73; -.
DR ProteomicsDB; 256578; -. [Q75N73-1]
DR ProteomicsDB; 330699; -.
DR Antibodypedia; 9517; 189 antibodies from 27 providers.
DR DNASU; 213053; -.
DR Ensembl; ENSMUST00000022688; ENSMUSP00000022688; ENSMUSG00000022094. [Q75N73-3]
DR Ensembl; ENSMUST00000068044; ENSMUSP00000066108; ENSMUSG00000022094. [Q75N73-1]
DR Ensembl; ENSMUST00000152067; ENSMUSP00000119040; ENSMUSG00000022094. [Q75N73-3]
DR GeneID; 213053; -.
DR KEGG; mmu:213053; -.
DR UCSC; uc007uns.1; mouse. [Q75N73-1]
DR CTD; 23516; -.
DR MGI; MGI:2384851; Slc39a14.
DR VEuPathDB; HostDB:ENSMUSG00000022094; -.
DR eggNOG; KOG2693; Eukaryota.
DR GeneTree; ENSGT00940000157986; -.
DR HOGENOM; CLU_015114_13_0_1; -.
DR InParanoid; Q75N73; -.
DR OMA; GHSHYSA; -.
DR OrthoDB; 657777at2759; -.
DR PhylomeDB; Q75N73; -.
DR TreeFam; TF318470; -.
DR Reactome; R-MMU-442380; Zinc influx into cells by the SLC39 gene family.
DR BioGRID-ORCS; 213053; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Slc39a14; mouse.
DR PRO; PR:Q75N73; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q75N73; protein.
DR Bgee; ENSMUSG00000022094; Expressed in gastrula and 256 other tissues.
DR ExpressionAtlas; Q75N73; baseline and differential.
DR Genevisible; Q75N73; MM.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015296; F:anion:cation symporter activity; IDA:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IDA:MGI.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; IMP:UniProtKB.
DR GO; GO:0002062; P:chondrocyte differentiation; IMP:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; IMP:UniProtKB.
DR GO; GO:0098739; P:import across plasma membrane; ISO:MGI.
DR GO; GO:0098662; P:inorganic cation transmembrane transport; IDA:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0033212; P:iron import into cell; IMP:UniProtKB.
DR GO; GO:0034755; P:iron ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006826; P:iron ion transport; IDA:MGI.
DR GO; GO:0055071; P:manganese ion homeostasis; IMP:UniProtKB.
DR GO; GO:0071421; P:manganese ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; IMP:UniProtKB.
DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0010817; P:regulation of hormone levels; IMP:UniProtKB.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; ISS:UniProtKB.
DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006829; P:zinc ion transport; IDA:MGI.
DR InterPro; IPR003689; ZIP.
DR Pfam; PF02535; Zip; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Endosome; Glycoprotein; Ion transport;
KW Lysosome; Membrane; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Transport; Ubl conjugation; Zinc; Zinc transport.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..489
FT /note="Metal cation symporter ZIP14"
FT /id="PRO_0000312195"
FT TOPO_DOM 29..155
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 156..176
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 177..184
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 185..205
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 206..221
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 222..242
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 243..349
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 350..370
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 371..394
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 395..415
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 416..421
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 422..442
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 443..457
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 458..478
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 479..489
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT MOTIF 248..255
FT /note="HHHGHXHX-motif"
FT /evidence="ECO:0000250|UniProtKB:Q15043"
FT MOTIF 373..378
FT /note="XEXPHE-motif"
FT /evidence="ECO:0000250|UniProtKB:Q15043"
FT CARBOHYD 52
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973,
FT ECO:0000269|PubMed:19656770"
FT CARBOHYD 75
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 85
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 100
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973,
FT ECO:0000269|PubMed:19656770"
FT VAR_SEQ 151..207
FT /note="VWGYGFLCVTVISLCSLMGASVVPFMKKTFYKRLLLYFIALAIGTLYSNALF
FT QLIPE -> VWGFGFLSVSLINLASLLGVLVLPCTEKAFFSRVLTYFIALSIGTLLSNA
FT LFQLIPE (in isoform 2)"
FT /id="VSP_060552"
FT MUTAGEN 438
FT /note="L->R: When overexpressed ubiquitously in conditional
FT knockin mice, perinatally lethal; when overexpressed in
FT osteoblasts in conditional knockin mice, produces a severe
FT skeletal phenotype marked by a drastic increase in cortical
FT thickness due to an enhanced endosteal bone formation; when
FT overexpressed in osteoclasts in conditional knockin mice,
FT no effect on bone hemostasis."
FT /evidence="ECO:0000269|PubMed:29621230"
FT CONFLICT 154
FT /note="Y -> F (in Ref. 3; AAH21530)"
FT /evidence="ECO:0000305"
FT CONFLICT 158..186
FT /note="CVTVISLCSLMGASVVPFMKKTFYKRLLL -> SVSLINLASLLGVLVLPCT
FT EKAFFSRVLT (in Ref. 3; AAH21530)"
FT /evidence="ECO:0000305"
FT CONFLICT 192
FT /note="A -> S (in Ref. 3; AAH21530)"
FT /evidence="ECO:0000305"
FT CONFLICT 197
FT /note="Y -> L (in Ref. 3; AAH21530)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 489 AA; 53962 MW; DB1F6F971A74D6FF CRC64;
MKRLHPALPS CLLLVLFGIW RTAPQTHASS AGLPPLSATS FLEDLMDRYG KNDSLTLTQL
KSLLDHLHVG VGRDNVSQPK EGPRNLSTCF SSGDLFAAHN LSERSQIGAS EFQEFCPTIL
QQLDSQACTS ENQKSEENEQ TEEGKPSAIE VWGYGFLCVT VISLCSLMGA SVVPFMKKTF
YKRLLLYFIA LAIGTLYSNA LFQLIPEAFG FNPQDNYVSK SAVVFGGFYL FFFTEKILKM
LLKQKNEHHH GHNHFTSETL PSKKDQEEGV TEKLQNGDLD HMIPQHCNSE LDGKAPGTDE
KVIVNSMSVQ DLQASQSACY WLKGVRYSDI GTLAWMITLS DGLHNFIDGL AIGASFTVSV
FQGISTSVAI LCEEFPHELG DFVILLNAGM SIQQALFFNF LSACCCYLGL AFGILAGSHF
SANWIFALAG GMFLYIALAD MFPEMNEVCQ EDEKNDSFLV PFVIQNLGLL TGFSIMLVLT
MYSGQIQIG
