ID AGR2_HUMAN Reviewed; 175 AA. AC O95994; DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 13-FEB-2019, entry version 138. DE RecName: Full=Anterior gradient protein 2 homolog; DE Short=AG-2; DE Short=hAG-2; DE AltName: Full=HPC8; DE AltName: Full=Secreted cement gland protein XAG-2 homolog; DE Flags: Precursor; GN Name=AGR2; Synonyms=AG2; ORFNames=UNQ515/PRO1030; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Mammary gland; RX PubMed=9790916; DOI=10.1006/bbrc.1998.9440; RA Thompson D.A., Weigel R.J.; RT "hAG-2, the human homologue of the Xenopus laevis cement gland gene RT XAG-2, is coexpressed with estrogen receptor in breast cancer cell RT lines."; RL Biochem. Biophys. Res. Commun. 251:111-116(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Prostatic carcinoma; RA Zhang J.S., Smith D.I.; RT "Identification of human homolog of XAG-2 over-expressed in tumors."; RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Fan Y.X., Yu L., Zhang X.N., Wan W.C., Wang X.K., Zhao S.Y.; RT "Cloning and expression of a novel human cDNA homology to murine GOB-4 RT mRNA."; RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases. RN [4] 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., RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., RA Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale RT effort to identify novel human secreted and transmembrane proteins: a RT bioinformatics assessment."; RL Genome Res. 13:2265-2270(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., RA Waterston R.H., Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 21-35. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [9] 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., RA Loader J.A., Daviet L., Legrain P., Parekh R., Harris A.L., RA Terrett J.A.; RT "hAG-2 and hAG-3, human homologues of genes involved in RT differentiation, are associated with oestrogen receptor-positive RT breast tumours and interact with metastasis gene C4.4a and RT dystroglycan."; RL Br. J. Cancer 88:579-585(2003). RN [10] RP SUBCELLULAR LOCATION. RX PubMed=15834940; DOI=10.1002/gcc.20188; RA Zhang J.-S., Gong A., Cheville J.C., Smith D.I., Young C.Y.F.; RT "AGR2, an androgen-inducible secretory protein overexpressed in RT prostate cancer."; RL Genes Chromosomes Cancer 43:249-259(2005). RN [11] RP FUNCTION. RX PubMed=18199544; DOI=10.1158/0008-5472.CAN-07-2930; RA Wang Z., Hao Y., Lowe A.W.; RT "The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, RT cell migration, and cellular transformation."; RL Cancer Res. 68:492-497(2008). RN [12] RP INTERACTION WITH MUC2, AND MUTAGENESIS OF CYS-81. RX PubMed=19359471; DOI=10.1073/pnas.0808722106; RA Park S.-W., Zhen G., Verhaeghe C., Nakagami Y., Nguyenvu L.T., RA Barczak A.J., Killeen N., Erle D.J.; RT "The protein disulfide isomerase AGR2 is essential for production of RT intestinal mucus."; RL Proc. Natl. Acad. Sci. U.S.A. 106:6950-6955(2009). RN [13] RP STRUCTURE BY NMR OF 41-175, FUNCTION, SUBUNIT, HOMODIMERIZATION, RP MUTAGENESIS OF GLU-60; TYR-63 AND LYS-64, AND CELL ADHESION REGION. RX PubMed=23274113; DOI=10.1016/j.jmb.2012.12.009; RA Patel P., Clarke C., Barraclough D.L., Jowitt T.A., Rudland P.S., RA Barraclough R., Lian L.Y.; RT "Metastasis-promoting anterior gradient 2 protein has a dimeric RT thioredoxin fold structure and a role in cell adhesion."; RL J. Mol. Biol. 425:929-943(2013). CC -!- FUNCTION: Required for MUC2 post-transcriptional synthesis and CC secretion. May play a role in the production of mucus by CC intestinal cells (By similarity). Proto-oncogene that may play a CC role in cell migration, cell differentiation and cell growth. CC Promotes cell adhesion (PubMed:23274113). {ECO:0000250, CC ECO:0000269|PubMed:18199544, ECO:0000269|PubMed:23274113}. CC -!- SUBUNIT: Monomer and homodimer (PubMed:23274113). Interacts with CC LYPD3 and DAG1 (alphaDAG1). Interacts with MUC2; disulfide-linked. CC {ECO:0000269|PubMed:12592373, ECO:0000269|PubMed:19359471, CC ECO:0000269|PubMed:23274113}. CC -!- INTERACTION: CC Q8NEC5:CATSPER1; NbExp=5; IntAct=EBI-712648, EBI-744545; CC P12104:FABP2; NbExp=6; IntAct=EBI-712648, EBI-3905109; CC Q15323:KRT31; NbExp=5; IntAct=EBI-712648, EBI-948001; CC Q02817:MUC2; NbExp=2; IntAct=EBI-712648, EBI-2105803; CC Q9H1M0:NUP62CL; NbExp=5; IntAct=EBI-712648, EBI-751933; CC Q96HA1:POM121; NbExp=4; IntAct=EBI-712648, EBI-739990; CC Q96EQ0:SGTB; NbExp=4; IntAct=EBI-712648, EBI-744081; CC Q9UMX0:UBQLN1; NbExp=7; IntAct=EBI-712648, EBI-741480; CC Q9UMX0-2:UBQLN1; NbExp=3; IntAct=EBI-712648, EBI-10173939; CC Q9UHD9:UBQLN2; NbExp=4; IntAct=EBI-712648, EBI-947187; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15834940}. CC Endoplasmic reticulum {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed strongly in trachea, lung, stomach, CC colon, prostate and small intestine. Expressed weakly in pituitary CC gland, salivary gland, mammary gland, bladder, appendix, ovary, CC fetal lung, uterus, pancreas, kidney, fetal kidney, testis, CC placenta, thyroid gland and in estrogen receptor (ER)-positive CC breast cancer cell lines. {ECO:0000269|PubMed:9790916}. CC -!- SIMILARITY: Belongs to the AGR family. {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; AF007791; AAC77358.1; -; mRNA. DR EMBL; AF038451; AAC82614.1; -; mRNA. DR EMBL; AF088867; AAF22484.1; -; mRNA. DR EMBL; AF115926; AAL54870.1; -; mRNA. DR EMBL; AF087879; AAP97179.1; -; mRNA. DR EMBL; AY359009; AAQ89368.1; -; mRNA. DR EMBL; BT007048; AAP35697.1; -; mRNA. DR EMBL; AC073333; AAP22354.1; -; Genomic_DNA. DR EMBL; BC015503; AAH15503.1; -; mRNA. DR CCDS; CCDS5364.1; -. DR PIR; JE0350; JE0350. DR RefSeq; NP_006399.1; NM_006408.3. DR RefSeq; XP_005249638.1; XM_005249581.4. DR UniGene; Hs.530009; -. DR PDB; 2LNS; NMR; -; A/B=41-175. DR PDB; 2LNT; NMR; -; A=41-175. DR PDBsum; 2LNS; -. DR PDBsum; 2LNT; -. DR ProteinModelPortal; O95994; -. DR SMR; O95994; -. DR BioGrid; 115802; 30. DR DIP; DIP-48825N; -. DR IntAct; O95994; 74. DR STRING; 9606.ENSP00000391490; -. DR iPTMnet; O95994; -. DR PhosphoSitePlus; O95994; -. DR BioMuta; AGR2; -. DR EPD; O95994; -. DR jPOST; O95994; -. DR PaxDb; O95994; -. DR PeptideAtlas; O95994; -. DR PRIDE; O95994; -. DR ProteomicsDB; 51169; -. DR TopDownProteomics; O95994; -. DR DNASU; 10551; -. DR Ensembl; ENST00000419304; ENSP00000391490; ENSG00000106541. DR GeneID; 10551; -. DR KEGG; hsa:10551; -. DR CTD; 10551; -. DR DisGeNET; 10551; -. DR EuPathDB; HostDB:ENSG00000106541.11; -. DR GeneCards; AGR2; -. DR HGNC; HGNC:328; AGR2. DR HPA; HPA007912; -. DR MIM; 606358; gene. DR neXtProt; NX_O95994; -. DR OpenTargets; ENSG00000106541; -. DR PharmGKB; PA24625; -. DR eggNOG; ENOG410IVR8; Eukaryota. DR eggNOG; ENOG4111K70; LUCA. DR GeneTree; ENSGT00530000063273; -. DR HOGENOM; HOG000231100; -. DR HOVERGEN; HBG006516; -. DR InParanoid; O95994; -. DR KO; K20356; -. DR OrthoDB; 1382017at2759; -. DR PhylomeDB; O95994; -. DR TreeFam; TF321449; -. DR ChiTaRS; AGR2; human. DR GeneWiki; AGR2; -. DR GenomeRNAi; 10551; -. DR PRO; PR:O95994; -. DR Proteomes; UP000005640; Chromosome 7. DR Bgee; ENSG00000106541; Expressed in 156 organ(s), highest expression level in mucosa of sigmoid colon. DR ExpressionAtlas; O95994; baseline and differential. DR Genevisible; O95994; HS. DR GO; GO:0005783; C:endoplasmic reticulum; IMP:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0002162; F:dystroglycan binding; IDA:UniProtKB. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IMP:UniProtKB. DR GO; GO:0048546; P:digestive tract morphogenesis; ISS:UniProtKB. DR GO; GO:0060480; P:lung goblet cell differentiation; IEA:Ensembl. DR GO; GO:0070254; P:mucus secretion; ISS:UniProtKB. DR GO; GO:0060548; P:negative regulation of cell death; IMP:UniProtKB. DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IMP:UniProtKB. DR GO; GO:0048639; P:positive regulation of developmental growth; ISS:UniProtKB. DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:1903896; P:positive regulation of IRE1-mediated unfolded protein response; IDA:UniProtKB. DR GO; GO:1903899; P:positive regulation of PERK-mediated unfolded protein response; IDA:UniProtKB. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IMP:UniProtKB. DR InterPro; IPR036249; Thioredoxin-like_sf. DR SUPFAM; SSF52833; SSF52833; 1. PE 1: Evidence at protein level; KW 3D-structure; Complete proteome; Direct protein sequencing; KW Disulfide bond; Endoplasmic reticulum; Proto-oncogene; KW Reference proteome; Secreted; Signal. FT SIGNAL 1 20 {ECO:0000269|PubMed:15340161}. FT CHAIN 21 175 Anterior gradient protein 2 homolog. FT /FTId=PRO_0000001037. FT REGION 21 40 Required to promote cell adhesion. FT {ECO:0000269|PubMed:23274113}. FT MOTIF 45 54 Homodimer stabilization; interchain. FT {ECO:0000244|PDB:2LNS, FT ECO:0000269|PubMed:23274113}. FT MOTIF 60 67 Homodimer stabilization; interchain. FT {ECO:0000244|PDB:2LNS, FT ECO:0000269|PubMed:23274113}. FT MUTAGEN 60 60 E->A: Monomer only, and reduced cell FT adhesion efficiency. FT {ECO:0000269|PubMed:23274113}. FT MUTAGEN 63 63 Y->A: Disrupted dimerization. FT {ECO:0000269|PubMed:23274113}. FT MUTAGEN 64 64 K->A: Disrupted dimerization. FT {ECO:0000269|PubMed:23274113}. FT MUTAGEN 81 81 C->S: Loss of interaction with MUC2. FT {ECO:0000269|PubMed:19359471}. FT STRAND 48 51 {ECO:0000244|PDB:2LNS}. FT HELIX 58 66 {ECO:0000244|PDB:2LNS}. FT TURN 67 69 {ECO:0000244|PDB:2LNS}. FT STRAND 72 77 {ECO:0000244|PDB:2LNS}. FT STRAND 79 81 {ECO:0000244|PDB:2LNS}. FT HELIX 82 91 {ECO:0000244|PDB:2LNS}. FT HELIX 95 102 {ECO:0000244|PDB:2LNS}. FT STRAND 103 105 {ECO:0000244|PDB:2LNS}. FT STRAND 109 111 {ECO:0000244|PDB:2LNT}. FT TURN 116 118 {ECO:0000244|PDB:2LNS}. FT STRAND 127 132 {ECO:0000244|PDB:2LNS}. FT TURN 133 135 {ECO:0000244|PDB:2LNS}. FT TURN 146 150 {ECO:0000244|PDB:2LNS}. FT TURN 154 156 {ECO:0000244|PDB:2LNS}. FT HELIX 157 167 {ECO:0000244|PDB:2LNS}. FT STRAND 171 173 {ECO:0000244|PDB:2LNT}. SQ SEQUENCE 175 AA; 19979 MW; F271B1BD377BEE11 CRC64; MEKIPVSAFL LLVALSYTLA RDTTVKPGAK KDTKDSRPKL PQTLSRGWGD QLIWTQTYEE ALYKSKTSNK PLMIIHHLDE CPHSQALKKV FAENKEIQKL AEQFVLLNLV YETTDKHLSP DGQYVPRIMF VDPSLTVRAD ITGRYSNRLY AYEPADTALL LDNMKKALKL LKTEL //