ID   AGR3_HUMAN              Reviewed;         166 AA.
AC   Q8TD06; A4D120;
DT   10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2002, sequence version 1.
DT   28-JAN-2026, entry version 152.
DE   RecName: Full=Anterior gradient protein 3;
DE            Short=AG-3;
DE            Short=AG3;
DE            Short=hAG-3;
DE   AltName: Full=Anterior gradient 3 homolog {ECO:0000312|HGNC:HGNC:24167};
DE   AltName: Full=Breast cancer membrane protein 11 {ECO:0000312|HGNC:HGNC:24167};
DE   AltName: Full=Protein disulfide isomerase family A, member 18 {ECO:0000312|HGNC:HGNC:24167};
DE   Flags: Precursor;
GN   Name=AGR3; Synonyms=BCMP11, PDIA18; ORFNames=UNQ642/PRO1272;
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 [MRNA].
RX   PubMed=12477722; DOI=10.1074/jbc.m210184200;
RA   Adam P.J., Boyd R., Tyson K.L., Fletcher G.C., Stamps A., Hudson L.,
RA   Poyser H.R., Redpath N., Griffiths M., Steers G., Harris A.L., Patel S.,
RA   Berry J., Loader J.A., Townsend R.R., Daviet L., Legrain P., Parekh R.,
RA   Terrett J.A.;
RT   "Comprehensive proteomic analysis of breast cancer cell membranes reveals
RT   unique proteins with potential roles in clinical cancer.";
RL   J. Biol. Chem. 278:6482-6489(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12690205; DOI=10.1126/science.1083423;
RA   Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA   Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA   Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA   Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA   Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA   Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA   Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA   Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA   Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA   Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA   Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA   Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA   Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA   Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA   Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA   Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA   Adams M.D., Tsui L.-C.;
RT   "Human chromosome 7: DNA sequence and biology.";
RL   Science 300:767-772(2003).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung;
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   PROTEIN SEQUENCE OF 22-36.
RX   PubMed=15340161; DOI=10.1110/ps.04682504;
RA   Zhang Z., Henzel W.J.;
RT   "Signal peptide prediction based on analysis of experimentally verified
RT   cleavage sites.";
RL   Protein Sci. 13:2819-2824(2004).
RN   [7]
RP   INTERACTION WITH LYPD3 AND DAG1.
RX   PubMed=12592373; DOI=10.1038/sj.bjc.6600740;
RA   Fletcher G.C., Patel S., Tyson K., Adam P.J., Schenker M., Loader J.A.,
RA   Daviet L., Legrain P., Parekh R., Harris A.L., Terrett J.A.;
RT   "hAG-2 and hAG-3, human homologues of genes involved in differentiation,
RT   are associated with oestrogen receptor-positive breast tumours and interact
RT   with metastasis gene C4.4a and dystroglycan.";
RL   Br. J. Cancer 88:579-585(2003).
RN   [8]
RP   SUBCELLULAR LOCATION, AND MUTAGENESIS OF 163-GLN--LEU-166.
RX   PubMed=18086916; DOI=10.1083/jcb.200705180;
RA   Raykhel I., Alanen H., Salo K., Jurvansuu J., Nguyen V.D., Latva-Ranta M.,
RA   Ruddock L.;
RT   "A molecular specificity code for the three mammalian KDEL receptors.";
RL   J. Cell Biol. 179:1193-1204(2007).
RN   [9]
RP   INDUCTION.
RX   PubMed=22361111; DOI=10.1016/j.jim.2012.01.013;
RA   Gray T.A., MacLaine N.J., Michie C.O., Bouchalova P., Murray E., Howie J.,
RA   Hrstka R., Maslon M.M., Nenutil R., Vojtesek B., Langdon S., Hayward L.,
RA   Gourley C., Hupp T.R.;
RT   "Anterior Gradient-3: a novel biomarker for ovarian cancer that mediates
RT   cisplatin resistance in xenograft models.";
RL   J. Immunol. Methods 378:20-32(2012).
RN   [10]
RP   INDUCTION.
RX   PubMed=23294566; DOI=10.1111/febs.12118;
RA   Bu H., Schweiger M.R., Manke T., Wunderlich A., Timmermann B., Kerick M.,
RA   Pasqualini L., Shehu E., Fuchsberger C., Cato A.C., Klocker H.;
RT   "Anterior gradient 2 and 3--two prototype androgen-responsive genes
RT   transcriptionally upregulated by androgens and by oestrogens in prostate
RT   cancer cells.";
RL   FEBS J. 280:1249-1266(2013).
RN   [11]
RP   TISSUE SPECIFICITY, INDUCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=25751668; DOI=10.1165/rcmb.2014-0318oc;
RA   Bonser L.R., Schroeder B.W., Ostrin L.A., Baumlin N., Olson J.L.,
RA   Salathe M., Erle D.J.;
RT   "The ER resident protein AGR3 is required for regulation of ciliary beat
RT   frequency in the airway.";
RL   Am. J. Respir. Cell Mol. Biol. 53:536-543(2015).
RN   [12]
RP   TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=26170690; DOI=10.2147/ott.s82235;
RA   Obacz J., Brychtova V., Podhorec J., Fabian P., Dobes P., Vojtesek B.,
RA   Hrstka R.;
RT   "Anterior gradient protein 3 is associated with less aggressive tumors and
RT   better outcome of breast cancer patients.";
RL   Onco Targets Ther. 8:1523-1532(2015).
RN   [13] {ECO:0007744|PDB:3PH9}
RP   X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 24-166.
RA   Nguyen V.D., Ruddock L.W., Salin M., Wierenga R.K.;
RT   "Crystal structure of the human anterior gradient protein 3.";
RL   Submitted (NOV-2010) to the PDB data bank.
CC   -!- FUNCTION: Required for calcium-mediated regulation of ciliary beat
CC       frequency and mucociliary clearance in the airway. Might be involved in
CC       the regulation of intracellular calcium in tracheal epithelial cells.
CC       {ECO:0000250|UniProtKB:Q8R3W7}.
CC   -!- SUBUNIT: Interacts with LYPD3 and DAG1 (alphaDAG1).
CC       {ECO:0000269|PubMed:12592373}.
CC   -!- INTERACTION:
CC       Q8TD06; Q10567-3: AP1B1; NbExp=3; IntAct=EBI-3925742, EBI-11978055;
CC       Q8TD06; Q8NEC5: CATSPER1; NbExp=3; IntAct=EBI-3925742, EBI-744545;
CC       Q8TD06; P15529-3: CD46; NbExp=3; IntAct=EBI-3925742, EBI-13046140;
CC       Q8TD06; Q99675: CGRRF1; NbExp=3; IntAct=EBI-3925742, EBI-2130213;
CC       Q8TD06; Q8NE01: CNNM3; NbExp=3; IntAct=EBI-3925742, EBI-741032;
CC       Q8TD06; Q6ICB0: DESI1; NbExp=3; IntAct=EBI-3925742, EBI-2806959;
CC       Q8TD06; Q9HAV5: EDA2R; NbExp=3; IntAct=EBI-3925742, EBI-526033;
CC       Q8TD06; O75477: ERLIN1; NbExp=6; IntAct=EBI-3925742, EBI-359299;
CC       Q8TD06; Q14802-3: FXYD3; NbExp=3; IntAct=EBI-3925742, EBI-12175685;
CC       Q8TD06; Q8IUC1: KRTAP11-1; NbExp=3; IntAct=EBI-3925742, EBI-1052037;
CC       Q8TD06; Q9H400: LIME1; NbExp=3; IntAct=EBI-3925742, EBI-2830566;
CC       Q8TD06; O15116: LSM1; NbExp=3; IntAct=EBI-3925742, EBI-347619;
CC       Q8TD06; Q8N4V1: MMGT1; NbExp=3; IntAct=EBI-3925742, EBI-6163737;
CC       Q8TD06; Q8IXM6: NRM; NbExp=3; IntAct=EBI-3925742, EBI-10262547;
CC       Q8TD06; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-3925742, EBI-741158;
CC       Q8TD06; P37198: NUP62; NbExp=6; IntAct=EBI-3925742, EBI-347978;
CC       Q8TD06; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-3925742, EBI-716063;
CC       Q8TD06; O60831: PRAF2; NbExp=3; IntAct=EBI-3925742, EBI-2506064;
CC       Q8TD06; A0A0S2Z4U3: SDC3; NbExp=3; IntAct=EBI-3925742, EBI-10204280;
CC       Q8TD06; O43765: SGTA; NbExp=6; IntAct=EBI-3925742, EBI-347996;
CC       Q8TD06; Q96EQ0: SGTB; NbExp=8; IntAct=EBI-3925742, EBI-744081;
CC       Q8TD06; O43278-2: SPINT1; NbExp=3; IntAct=EBI-3925742, EBI-12078338;
CC       Q8TD06; Q9NPL8: TIMMDC1; NbExp=3; IntAct=EBI-3925742, EBI-6268651;
CC       Q8TD06; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-3925742, EBI-8638294;
CC       Q8TD06; Q9UMX0: UBQLN1; NbExp=4; IntAct=EBI-3925742, EBI-741480;
CC       Q8TD06; Q9UMX0-2: UBQLN1; NbExp=3; IntAct=EBI-3925742, EBI-10173939;
CC       Q8TD06; Q9UHD9: UBQLN2; NbExp=6; IntAct=EBI-3925742, EBI-947187;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC       {ECO:0000269|PubMed:18086916, ECO:0000269|PubMed:25751668}. Note=Found
CC       in the cytoplasm, which could include the endoplasmic reticulum.
CC       {ECO:0000305|PubMed:26170690}.
CC   -!- TISSUE SPECIFICITY: Expressed in the lung, in the ciliated cells of the
CC       airway epithelium (PubMed:25751668). Expression increased with
CC       differentiation of airway epithelial cells (PubMed:25751668). Not
CC       detected in the mucous cells (PubMed:25751668). Expressed in ciliated
CC       cells in the oviduct (PubMed:26170690). Also detected in stomach,
CC       colon, prostate and liver (PubMed:25751668). Expressed in breast,
CC       ovary, prostate and liver cancer (PubMed:26170690). Expression is
CC       associated with the level of differentiation of breast cancer (at
CC       protein level) (PubMed:26170690). {ECO:0000269|PubMed:25751668,
CC       ECO:0000269|PubMed:26170690}.
CC   -!- INDUCTION: Not induced as part of the cellular response to endoplasmic
CC       reticulum stress (PubMed:25751668). Up-regulated by androgens and by
CC       estrogens in prostate cancer cells (PubMed:23294566) Up-regulated by a
CC       hormone (estrogen-receptor alpha) independent mechanism in ovarian
CC       cancer (PubMed:22361111). {ECO:0000269|PubMed:22361111,
CC       ECO:0000269|PubMed:23294566, ECO:0000269|PubMed:25751668}.
CC   -!- SIMILARITY: Belongs to the AGR family. {ECO:0000305}.
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DR   EMBL; AY069977; AAL55402.1; -; mRNA.
DR   EMBL; AY359065; AAQ89424.1; -; mRNA.
DR   EMBL; CH236948; EAL24282.1; -; Genomic_DNA.
DR   EMBL; CH471073; EAW93685.1; -; Genomic_DNA.
DR   EMBL; BC058284; AAH58284.1; -; mRNA.
DR   CCDS; CCDS5365.1; -.
DR   RefSeq; NP_789783.1; NM_176813.5.
DR   RefSeq; XP_047275884.1; XM_047419928.1.
DR   RefSeq; XP_054213338.1; XM_054357363.1.
DR   PDB; 3PH9; X-ray; 1.83 A; A/B=24-166.
DR   PDBsum; 3PH9; -.
DR   AlphaFoldDB; Q8TD06; -.
DR   SMR; Q8TD06; -.
DR   BioGRID; 127586; 43.
DR   FunCoup; Q8TD06; 31.
DR   IntAct; Q8TD06; 34.
DR   MINT; Q8TD06; -.
DR   STRING; 9606.ENSP00000308606; -.
DR   GlyCosmos; Q8TD06; 3 sites, 1 glycan.
DR   GlyGen; Q8TD06; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; Q8TD06; -.
DR   PhosphoSitePlus; Q8TD06; -.
DR   BioMuta; AGR3; -.
DR   DMDM; 66774045; -.
DR   jPOST; Q8TD06; -.
DR   MassIVE; Q8TD06; -.
DR   PaxDb; 9606-ENSP00000308606; -.
DR   PeptideAtlas; Q8TD06; -.
DR   ProteomicsDB; 74205; -.
DR   Antibodypedia; 25286; 288 antibodies from 33 providers.
DR   DNASU; 155465; -.
DR   Ensembl; ENST00000310398.7; ENSP00000308606.2; ENSG00000173467.10.
DR   GeneID; 155465; -.
DR   KEGG; hsa:155465; -.
DR   MANE-Select; ENST00000310398.7; ENSP00000308606.2; NM_176813.5; NP_789783.1.
DR   UCSC; uc003sts.4; human.
DR   AGR; HGNC:24167; -.
DR   ClinPGx; PA162375917; -.
DR   CTD; 155465; -.
DR   DisGeNET; 155465; -.
DR   GeneCards; AGR3; -.
DR   HGNC; HGNC:24167; AGR3.
DR   HPA; ENSG00000173467; Tissue enhanced (fallopian tube, intestine, lung).
DR   MIM; 609482; gene.
DR   OpenTargets; ENSG00000173467; -.
DR   VEuPathDB; HostDB:ENSG00000173467; -.
DR   eggNOG; ENOG502R72A; Eukaryota.
DR   GeneTree; ENSGT00530000063273; -.
DR   HOGENOM; CLU_088048_1_0_1; -.
DR   InParanoid; Q8TD06; -.
DR   OMA; PILIENM; -.
DR   OrthoDB; 262308at2759; -.
DR   PAN-GO; Q8TD06; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; Q8TD06; -.
DR   PathwayCommons; Q8TD06; -.
DR   SignaLink; Q8TD06; -.
DR   Agora; ENSG00000173467; -.
DR   BioGRID-ORCS; 155465; 42 hits in 1107 CRISPR screens.
DR   ChiTaRS; AGR3; human.
DR   EvolutionaryTrace; Q8TD06; -.
DR   GeneWiki; AGR3; -.
DR   GenomeRNAi; 155465; -.
DR   Pharos; Q8TD06; Tbio.
DR   PRO; PR:Q8TD06; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q8TD06; protein.
DR   Bgee; ENSG00000173467; Expressed in bronchial epithelial cell and 128 other cell types or tissues.
DR   ExpressionAtlas; Q8TD06; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR   GO; GO:0002162; F:dystroglycan binding; IDA:UniProtKB.
DR   CDD; cd02960; AGR; 1.
DR   FunFam; 3.40.30.10:FF:000036; anterior gradient protein 2 homolog; 1.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 1.
DR   InterPro; IPR051099; AGR/TXD.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   PANTHER; PTHR15337:SF5; ANTERIOR GRADIENT PROTEIN 3; 1.
DR   PANTHER; PTHR15337; ANTERIOR GRADIENT PROTEIN-RELATED; 1.
DR   Pfam; PF13899; Thioredoxin_7; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Direct protein sequencing; Endoplasmic reticulum;
KW   Proteomics identification; Reference proteome; Signal.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000269|PubMed:15340161"
FT   CHAIN           22..166
FT                   /note="Anterior gradient protein 3"
FT                   /id="PRO_0000001040"
FT   MOTIF           163..166
FT                   /note="Prevents secretion from ER"
FT                   /evidence="ECO:0000269|PubMed:18086916"
FT   MUTAGEN         163..166
FT                   /note="Missing: Leads to Golgi localization;."
FT                   /evidence="ECO:0000269|PubMed:18086916"
FT   STRAND          33..35
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           48..58
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   STRAND          62..66
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           72..83
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           85..93
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   STRAND          96..102
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           107..109
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   STRAND          116..122
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           145..147
FT                   /evidence="ECO:0007829|PDB:3PH9"
FT   HELIX           148..159
FT                   /evidence="ECO:0007829|PDB:3PH9"
SQ   SEQUENCE   166 AA;  19171 MW;  B1A4804B47705D65 CRC64;
     MMLHSALGLC LLLVTVSSNL AIAIKKEKRP PQTLSRGWGD DITWVQTYEE GLFYAQKSKK
     PLMVIHHLED CQYSQALKKV FAQNEEIQEM AQNKFIMLNL MHETTDKNLS PDGQYVPRIM
     FVDPSLTVRA DIAGRYSNRL YTYEPRDLPL LIENMKKALR LIQSEL
//