ID CLD18_MOUSE Reviewed; 264 AA. AC P56857; Q91ZY9; Q91ZZ0; Q91ZZ1; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2000, sequence version 1. DT 22-FEB-2023, entry version 146. DE RecName: Full=Claudin-18; GN Name=Cldn18; 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], SUBCELLULAR LOCATION, TISSUE SPECIFICITY RP (ISOFORMS A1.1; A1.2; A2.1 AND A2.2), AND ALTERNATIVE SPLICING. RX PubMed=11585919; DOI=10.1128/mcb.21.21.7380-7390.2001; RA Niimi T., Nagashima K., Ward J.M., Minoo P., Zimonjic D.B., Popescu N.C., RA Kimura S.; RT "Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 RT homeodomain transcription factor, encodes lung- and stomach-specific RT isoforms through alternative splicing."; RL Mol. Cell. Biol. 21:7380-7390(2001). RN [2] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-217, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Lung; 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 [3] RP FUNCTION (ISOFORM 2.1), SUBCELLULAR LOCATION (ISOFORMS A1.1 AND A2.1), RP TISSUE SPECIFICITY (ISOFORMS A1.1 AND A2.1), AND DISRUPTION RP PHENOTYPE(ISOFORM A2.1). RX PubMed=22079592; DOI=10.1053/j.gastro.2011.10.040; RA Hayashi D., Tamura A., Tanaka H., Yamazaki Y., Watanabe S., Suzuki K., RA Suzuki K., Sentani K., Yasui W., Rakugi H., Isaka Y., Tsukita S.; RT "Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of RT interleukin-1beta, and atrophic gastritis in mice."; RL Gastroenterology 142:292-304(2012). RN [4] RP FUNCTION, INTERACTION WITH TJP2, TISSUE SPECIFICITY (ISOFORMS A1.1 AND RP A2.1), AND DISRUPTION PHENOTYPE. RX PubMed=22437732; DOI=10.1002/jbmr.1600; RA Linares G.R., Brommage R., Powell D.R., Xing W., Chen S.T., Alshbool F.Z., RA Lau K.H., Wergedal J.E., Mohan S.; RT "Claudin 18 is a novel negative regulator of bone resorption and osteoclast RT differentiation."; RL J. Bone Miner. Res. 27:1553-1565(2012). RN [5] RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION RP PHENOTYPE. RX PubMed=24787463; DOI=10.1165/rcmb.2013-0456oc; RA LaFemina M.J., Sutherland K.M., Bentley T., Gonzales L.W., Allen L., RA Chapin C.J., Rokkam D., Sweerus K.A., Dobbs L.G., Ballard P.L., Frank J.A.; RT "Claudin-18 deficiency results in alveolar barrier dysfunction and impaired RT alveologenesis in mice."; RL Am. J. Respir. Cell Mol. Biol. 51:550-558(2014). CC -!- FUNCTION: Plays a major role in tight junction-specific obliteration of CC the intercellular space, through calcium-independent cell-adhesion CC activity (By similarity). Required for lung alveolarization and CC maintenance of the paracellular alveolar epithelial barrier CC (PubMed:24787463). Acts as a negative regulator of RANKL-induced CC osteoclast differentiation, potentially via relocation of TJP2/ZO-2 CC away from the nucleus, subsequently involved in bone resorption in CC response to calcium deficiency (PubMed:22437732). CC {ECO:0000250|UniProtKB:O88552, ECO:0000269|PubMed:22437732, CC ECO:0000269|PubMed:24787463}. CC -!- FUNCTION: [Isoform A2.1]: Required for the formation of the gastric CC paracellular barrier via its role in tight junction formation, thereby CC involved in the response to gastric acidification. CC {ECO:0000269|PubMed:22079592}. CC -!- SUBUNIT: Interacts with TJP2/ZO-2. {ECO:0000269|PubMed:22437732}. CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction CC {ECO:0000269|PubMed:11585919}. Cell membrane CC {ECO:0000269|PubMed:11585919}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localizes to tight junctions in epithelial cells. CC {ECO:0000269|PubMed:11585919}. CC -!- SUBCELLULAR LOCATION: [Isoform A1.1]: Cell junction, tight junction CC {ECO:0000269|PubMed:22079592}. CC -!- SUBCELLULAR LOCATION: [Isoform A2.1]: Cell junction, tight junction CC {ECO:0000269|PubMed:22079592}. Lateral cell membrane CC {ECO:0000269|PubMed:22079592}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=A1.1; Synonyms=Lung-type {ECO:0000303|PubMed:22079592}; CC IsoId=P56857-1; Sequence=Displayed; CC Name=A1.2; CC IsoId=P56857-2; Sequence=VSP_001104, VSP_001105; CC Name=A2.1; Synonyms=Stomach-type {ECO:0000303|PubMed:22079592}; CC IsoId=P56857-3; Sequence=VSP_001103; CC Name=A2.2; CC IsoId=P56857-4; Sequence=VSP_001103, VSP_001104, VSP_001105; CC -!- TISSUE SPECIFICITY: Expressed in the lung (at protein level). CC {ECO:0000269|PubMed:24787463}. CC -!- TISSUE SPECIFICITY: [Isoform A1.1]: Expressed in lung (PubMed:11585919, CC PubMed:22437732). Expressed in the stomach (PubMed:22079592). CC {ECO:0000269|PubMed:11585919, ECO:0000269|PubMed:22079592, CC ECO:0000269|PubMed:22437732}. CC -!- TISSUE SPECIFICITY: [Isoform A1.2]: Expressed in lung. CC {ECO:0000269|PubMed:11585919}. CC -!- TISSUE SPECIFICITY: [Isoform A2.1]: Expressed in stomach CC (PubMed:11585919, PubMed:22079592, PubMed:22437732). Expressed in bone CC (PubMed:22437732). {ECO:0000269|PubMed:11585919, CC ECO:0000269|PubMed:22079592, ECO:0000269|PubMed:22437732}. CC -!- TISSUE SPECIFICITY: [Isoform A2.2]: Expressed in stomach. CC {ECO:0000269|PubMed:11585919}. CC -!- DEVELOPMENTAL STAGE: Expressed in the lungs from 19 dpc, expression is CC increased at birth and at four weeks of age. CC {ECO:0000269|PubMed:24787463}. CC -!- DISRUPTION PHENOTYPE: Increase in bronchoalveolar lavage fluid leakage CC as a result of alveolar epithelial cell injury at P3 and four weeks of CC age, resulting in an increase in AT2 cells in the lungs by four weeks CC of age (PubMed:24787463). Increase in expression of CLDN3 and CLDN4 in CC lungs at P7 (PubMed:24787463). Fixed alveolar permeability defect and CC dysregulation of genes involved in lung development in lung tissue, CC including AREG, SHH, ELN, VEGFA, FGFR4, and ADM from 4 weeks of age CC (PubMed:24787463). Impaired alveolarization and decreased lung surface CC area at four weeks of age (PubMed:24787463). Membrane ruffling and CC splaying is evident at AT1-AT1 cell junctions at 8 weeks of age CC (PubMed:24787463). Histological abnormalities in the gastric mucosa CC including inflammatory infiltrates and a decrease in the number of CC well-differentiated gastric chief cells and parietal cells CC (PubMed:22437732). Reduced total body bone mineral content, total body CC bone mineral density (BMD), cortical bone thickness, vertebra BMD and CC femur BMD by 20-25% from 4 to 26 weeks of age (PubMed:22437732). CC Reduced trabecular bone, trabecular thickness and trabecular number CC decreased by 50%, whereas trabecular spacing is increased by 50% from 4 CC to 26 weeks of age (PubMed:22437732). Significant increase in CC osteoclastogenesis, osteoclast number and number of nuclei in CC osteoclasts on the surface of the trabecular bone of the proximal tibia CC (PubMed:22437732). Decrease in bone mass density in the femur, lumbar CC and whole body (PubMed:22437732). Skeletal defects and osteoclast CC levels were exacerbated significantly by a calcium depleted diet CC (PubMed:22437732). {ECO:0000269|PubMed:22437732, CC ECO:0000269|PubMed:24787463}. CC -!- DISRUPTION PHENOTYPE: [Isoform A2.1]: 100% incidence of chronic CC gastritis with atypical distribution of cells in the gastric gland, CC including fewer parietal and chief cells that are replaced by CC metaplastic cells with dilated gland lumina (PubMed:22079592). Lack of CC increase in stomach lumen acidification with age (PubMed:22079592). CC Lack of sensitivity to gastric acidity and an increase in ion CC permeability of the gastric paracellular barrier (PubMed:22079592). CC Spasmolytic polypeptide-expressing metaplasia cells are dominant in the CC stomach in place of well-differentiated parietal cells and chief cells CC (PubMed:22079592). Abundant inflammatory cells in the submucosal region CC (PubMed:22079592). Slight decrease in the localization of CLDN18 CC isoform A1.1 at tight junctions in the gastric superficial mucous CC epithelial cells (PubMed:22079592). Upper apical layer of tight CC junctions in the stomach missing resulting in a decrease in tight CC junction width (PubMed:22079592). Increase in proinflammatory markers CC IL1B and TNF/TNF-A, the chemoattractant CXCL1/KC and prostaglandin E2 CC inflammatory marker PTGS2/COX2 in gastric tissue (PubMed:22079592). CC {ECO:0000269|PubMed:22079592}. CC -!- SIMILARITY: Belongs to the claudin 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; AF221068; AAF26447.1; -; mRNA. DR EMBL; AF349450; AAL15635.1; -; mRNA. DR EMBL; AF349451; AAL15636.1; -; mRNA. DR EMBL; AF349453; AAL15638.1; -; mRNA. DR CCDS; CCDS23437.1; -. [P56857-1] DR CCDS; CCDS57692.1; -. [P56857-2] DR CCDS; CCDS57693.1; -. [P56857-4] DR CCDS; CCDS57694.1; -. [P56857-3] DR RefSeq; NP_001181850.1; NM_001194921.1. [P56857-3] DR RefSeq; NP_001181851.1; NM_001194922.1. [P56857-2] DR RefSeq; NP_001181852.1; NM_001194923.1. [P56857-4] DR RefSeq; NP_062789.1; NM_019815.3. [P56857-1] DR AlphaFoldDB; P56857; -. DR SMR; P56857; -. DR DIP; DIP-48956N; -. DR IntAct; P56857; 2. DR STRING; 10090.ENSMUSP00000035048; -. DR TCDB; 1.H.1.1.8; the claudin tight junction (claudin1) family. DR iPTMnet; P56857; -. DR PhosphoSitePlus; P56857; -. DR MaxQB; P56857; -. DR PaxDb; P56857; -. DR ProteomicsDB; 285482; -. [P56857-1] DR ProteomicsDB; 285483; -. [P56857-2] DR ProteomicsDB; 285484; -. [P56857-3] DR ProteomicsDB; 285485; -. [P56857-4] DR Antibodypedia; 4575; 229 antibodies from 29 providers. DR DNASU; 56492; -. DR Ensembl; ENSMUST00000035048.12; ENSMUSP00000035048.6; ENSMUSG00000032473.14. DR Ensembl; ENSMUST00000112882.9; ENSMUSP00000108503.3; ENSMUSG00000032473.14. [P56857-3] DR Ensembl; ENSMUST00000131922.2; ENSMUSP00000117382.2; ENSMUSG00000032473.14. [P56857-4] DR Ensembl; ENSMUST00000136429.8; ENSMUSP00000115782.2; ENSMUSG00000032473.14. [P56857-2] DR GeneID; 56492; -. DR KEGG; mmu:56492; -. DR UCSC; uc009rep.2; mouse. [P56857-1] DR UCSC; uc009req.2; mouse. [P56857-2] DR UCSC; uc009rer.2; mouse. [P56857-4] DR UCSC; uc009res.2; mouse. [P56857-3] DR AGR; MGI:1929209; -. DR CTD; 51208; -. DR MGI; MGI:1929209; Cldn18. DR VEuPathDB; HostDB:ENSMUSG00000032473; -. DR eggNOG; ENOG502QTRB; Eukaryota. DR GeneTree; ENSGT00940000158655; -. DR HOGENOM; CLU_076370_2_1_1; -. DR InParanoid; P56857; -. DR OMA; TICQVMG; -. DR OrthoDB; 5346296at2759; -. DR PhylomeDB; P56857; -. DR TreeFam; TF331936; -. DR BioGRID-ORCS; 56492; 1 hit in 78 CRISPR screens. DR PRO; PR:P56857; -. DR Proteomes; UP000000589; Chromosome 9. DR RNAct; P56857; protein. DR Bgee; ENSMUSG00000032473; Expressed in mucous cell of stomach and 25 other tissues. DR Genevisible; P56857; MM. DR GO; GO:0005923; C:bicellular tight junction; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0070160; C:tight junction; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro. DR GO; GO:0070830; P:bicellular tight junction assembly; IBA:GO_Central. DR GO; GO:0016338; P:calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules; ISS:UniProtKB. DR GO; GO:0007155; P:cell adhesion; IBA:GO_Central. DR GO; GO:0048565; P:digestive tract development; IMP:MGI. DR GO; GO:0045779; P:negative regulation of bone resorption; IMP:MGI. DR GO; GO:2001205; P:negative regulation of osteoclast development; IMP:MGI. DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; IDA:MGI. DR GO; GO:0034504; P:protein localization to nucleus; IDA:MGI. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0120192; P:tight junction assembly; IMP:UniProtKB. DR GO; GO:0071847; P:TNFSF11-mediated signaling pathway; IMP:MGI. DR Gene3D; 1.20.140.150; -; 1. DR InterPro; IPR006187; Claudin. DR InterPro; IPR003928; Claudin18. DR InterPro; IPR017974; Claudin_CS. DR InterPro; IPR004031; PMP22/EMP/MP20/Claudin. DR PANTHER; PTHR12002; CLAUDIN; 1. DR PANTHER; PTHR12002:SF9; CLAUDIN-18; 1. DR Pfam; PF00822; PMP22_Claudin; 1. DR PRINTS; PR01077; CLAUDIN. DR PRINTS; PR01448; CLAUDIN18. DR PROSITE; PS01346; CLAUDIN; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cell junction; Cell membrane; Membrane; KW Phosphoprotein; Reference proteome; Tight junction; Transmembrane; KW Transmembrane helix. FT CHAIN 1..264 FT /note="Claudin-18" FT /id="PRO_0000457666" FT TOPO_DOM 1..6 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 7..27 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 28..80 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 81..101 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 102..122 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 123..143 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 144..176 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 177..197 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 198..264 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 198..264 FT /note="Required for role in regulation of RANKL-induced FT osteoclast differentiation" FT /evidence="ECO:0000269|PubMed:22437732" FT REGION 241..264 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 244..264 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 217 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT VAR_SEQ 1..69 FT /note="MATTTCQVVGLLLSLLGLAGCIAATGMDMWSTQDLYDNPVTAVFQYEGLWRS FT CVQQSSGFTECRPYFTI -> MSVTACQGLGFVVSLIGFAGIIAATCMDQWSTQDLYNN FT PVTAVFNYQGLWRSCVRESSGFTECRGYFTL (in isoform A2.1 and FT isoform A2.2)" FT /evidence="ECO:0000305" FT /id="VSP_001103" FT VAR_SEQ 208 FT /note="N -> K (in isoform A1.2 and isoform A2.2)" FT /evidence="ECO:0000305" FT /id="VSP_001104" FT VAR_SEQ 209..264 FT /note="Missing (in isoform A1.2 and isoform A2.2)" FT /evidence="ECO:0000305" FT /id="VSP_001105" SQ SEQUENCE 264 AA; 28122 MW; 3CA0D441C4705653 CRC64; MATTTCQVVG LLLSLLGLAG CIAATGMDMW STQDLYDNPV TAVFQYEGLW RSCVQQSSGF TECRPYFTIL GLPAMLQAVR ALMIVGIVLG VIGILVSIFA LKCIRIGSMD DSAKAKMTLT SGILFIISGI CAIIGVSVFA NMLVTNFWMS TANMYSGMGG MGGMVQTVQT RYTFGAALFV GWVAGGLTLI GGVMMCIACR GLTPDDSNFK AVSYHASGQN VAYRPGGFKA STGFGSNTRN KKIYDGGART EDDEQSHPTK YDYV //