ID CLD18_HUMAN Reviewed; 261 AA. AC P56856; A5PL21; Q96PH4; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2000, sequence version 1. DT 09-APR-2025, entry version 182. DE RecName: Full=Claudin-18; GN Name=CLDN18; ORFNames=UNQ778/PRO1572; 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], 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A1). 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]. 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A1). 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 [5] RP TISSUE SPECIFICITY (ISOFORMS A1 AND A2). RX PubMed=19047087; DOI=10.1158/1078-0432.ccr-08-1547; RA Sahin U., Koslowski M., Dhaene K., Usener D., Brandenburg G., Seitz G., RA Huber C., Tuereci O.; RT "Claudin-18 splice variant 2 is a pan-cancer target suitable for RT therapeutic antibody development."; RL Clin. Cancer Res. 14:7624-7634(2008). RN [6] RP INTERACTION WITH CLDN19 (ISOFORM A1). RX PubMed=19706394; DOI=10.1073/pnas.0907724106; RA Hou J., Renigunta A., Gomes A.S., Hou M., Paul D.L., Waldegger S., RA Goodenough D.A.; RT "Claudin-16 and claudin-19 interaction is required for their assembly into RT tight junctions and for renal reabsorption of magnesium."; RL Proc. Natl. Acad. Sci. U.S.A. 106:15350-15355(2009). RN [7] RP DEVELOPMENTAL STAGE. 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: Involved in alveolar fluid homeostasis via regulation of CC alveolar epithelial tight junction composition and therefore ion CC transport and solute permeability, potentially via downstream CC regulation of the actin cytoskeleton organization and beta-2-adrenergic CC signaling (By similarity). Required for lung alveolarization and CC maintenance of the paracellular alveolar epithelial barrier (By CC similarity). Acts to maintain epithelial progenitor cell proliferation CC and organ size, via regulation of YAP1 localization away from the CC nucleus and thereby restriction of YAP1 target gene transcription (By CC similarity). Acts as a negative regulator of RANKL-induced osteoclast CC differentiation, potentially via relocation of TJP2/ZO-2 away from the CC nucleus, subsequently involved in bone resorption in response to CC calcium deficiency (By similarity). Mediates the osteoprotective CC effects of estrogen, potentially via acting downstream of estrogen CC signaling independently of RANKL signaling pathways (By similarity). CC {ECO:0000250|UniProtKB:P56857}. CC -!- FUNCTION: [Isoform A1]: Involved in the maintenance of homeostasis of CC the alveolar microenvironment via regulation of pH and subsequent T- CC cell activation in the alveolar space, is therefore indirectly involved CC in limiting C.neoformans infection. {ECO:0000250|UniProtKB:P56857}. CC -!- FUNCTION: [Isoform A2]: 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:0000250|UniProtKB:P56857}. CC -!- SUBUNIT: Interacts with TJP2/ZO-2 (By similarity). Interacts with CC TJP1/ZO-1 (By similarity). Interacts with YAP1 (phosphorylated); the CC interaction sequesters YAP1 away from the nucleus and thereby restricts CC transcription of YAP1 target genes (By similarity). CC {ECO:0000250|UniProtKB:P56857}. CC -!- SUBUNIT: [Isoform A1]: Interacts with CLDN19. CC {ECO:0000269|PubMed:19706394}. CC -!- INTERACTION: CC P56856; Q08426: EHHADH; NbExp=3; IntAct=EBI-16354902, EBI-2339219; CC P56856; Q01453: PMP22; NbExp=3; IntAct=EBI-16354902, EBI-2845982; CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction CC {ECO:0000250|UniProtKB:P56857}. Cell membrane CC {ECO:0000250|UniProtKB:P56857}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localizes to tight junctions in epithelial cells. CC {ECO:0000250|UniProtKB:P56857}. CC -!- SUBCELLULAR LOCATION: [Isoform A1]: Cell junction, tight junction CC {ECO:0000250|UniProtKB:P56857}. CC -!- SUBCELLULAR LOCATION: [Isoform A2]: Cell junction, tight junction CC {ECO:0000250|UniProtKB:P56857}. Lateral cell membrane CC {ECO:0000250|UniProtKB:P56857}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=A1 {ECO:0000303|PubMed:11585919}; Synonyms=CLDN18.1 CC {ECO:0000303|PubMed:19047087}; CC IsoId=P56856-1; Sequence=Displayed; CC Name=A2 {ECO:0000303|PubMed:11585919}; Synonyms=CLDN18.2 CC {ECO:0000303|PubMed:19047087}; CC IsoId=P56856-2; Sequence=VSP_001102; CC -!- TISSUE SPECIFICITY: [Isoform A1]: Expression is restricted to the lung. CC {ECO:0000269|PubMed:19047087}. CC -!- TISSUE SPECIFICITY: [Isoform A2]: Expression is restricted to the CC stomach mucosa where it is predominantly observed in the epithelial CC cells of the pit region and the base of the gastric glands including CC exocrine and endocrine cells (at protein level). CC {ECO:0000269|PubMed:19047087}. CC -!- DEVELOPMENTAL STAGE: Expressed in the lungs from 23 weeks onwards, CC expression increases during the third trimester resulting in CC significantly higher expression at birth. CC {ECO:0000269|PubMed:24787463}. 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; AF221069; AAF26448.1; -; mRNA. DR EMBL; AF349452; AAL15637.1; -; mRNA. DR EMBL; AY358479; AAQ88843.1; -; mRNA. DR EMBL; CH471052; EAW79092.1; -; Genomic_DNA. DR EMBL; BC142708; AAI42709.1; -; mRNA. DR EMBL; BC146668; AAI46669.1; -; mRNA. DR CCDS; CCDS3095.1; -. [P56856-1] DR CCDS; CCDS33862.1; -. [P56856-2] DR RefSeq; NP_001002026.1; NM_001002026.3. [P56856-2] DR RefSeq; NP_057453.1; NM_016369.4. [P56856-1] DR AlphaFoldDB; P56856; -. DR SMR; P56856; -. DR BioGRID; 119381; 37. DR DIP; DIP-48955N; -. DR IntAct; P56856; 6. DR STRING; 9606.ENSP00000340939; -. DR ChEMBL; CHEMBL3712859; -. DR GlyConnect; 2029; 1 N-Linked glycan (1 site). DR GlyCosmos; P56856; 1 site, 2 glycans. DR GlyGen; P56856; 1 site, 2 N-linked glycans (1 site). DR iPTMnet; P56856; -. DR PhosphoSitePlus; P56856; -. DR BioMuta; CLDN18; -. DR DMDM; 7387578; -. DR MassIVE; P56856; -. DR PaxDb; 9606-ENSP00000183605; -. DR PeptideAtlas; P56856; -. DR ProteomicsDB; 56953; -. [P56856-1] DR ProteomicsDB; 56954; -. [P56856-2] DR ABCD; P56856; 33 sequenced antibodies. DR Antibodypedia; 4575; 385 antibodies from 33 providers. DR DNASU; 51208; -. DR Ensembl; ENST00000183605.10; ENSP00000183605.5; ENSG00000066405.13. [P56856-1] DR Ensembl; ENST00000343735.8; ENSP00000340939.4; ENSG00000066405.13. [P56856-2] DR GeneID; 51208; -. DR KEGG; hsa:51208; -. DR MANE-Select; ENST00000183605.10; ENSP00000183605.5; NM_016369.4; NP_057453.1. DR UCSC; uc003ero.2; human. [P56856-1] DR AGR; HGNC:2039; -. DR CTD; 51208; -. DR DisGeNET; 51208; -. DR GeneCards; CLDN18; -. DR HGNC; HGNC:2039; CLDN18. DR HPA; ENSG00000066405; Group enriched (lung, stomach). DR MIM; 609210; gene. DR neXtProt; NX_P56856; -. DR OpenTargets; ENSG00000066405; -. DR PharmGKB; PA26565; -. DR VEuPathDB; HostDB:ENSG00000066405; -. DR eggNOG; ENOG502QTRB; Eukaryota. DR GeneTree; ENSGT00940000158655; -. DR HOGENOM; CLU_076370_2_1_1; -. DR InParanoid; P56856; -. DR OMA; TICQVMG; -. DR OrthoDB; 8795554at2759; -. DR PhylomeDB; P56856; -. DR TreeFam; TF331936; -. DR PathwayCommons; P56856; -. DR Reactome; R-HSA-420029; Tight junction interactions. DR SignaLink; P56856; -. DR BioGRID-ORCS; 51208; 14 hits in 1139 CRISPR screens. DR ChiTaRS; CLDN18; human. DR GeneWiki; CLDN18; -. DR GenomeRNAi; 51208; -. DR Pharos; P56856; Tbio. DR PRO; PR:P56856; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P56856; protein. DR Bgee; ENSG00000066405; Expressed in pylorus and 138 other cell types or tissues. DR ExpressionAtlas; P56856; baseline and differential. DR GO; GO:0005923; C:bicellular tight junction; ISS:UniProtKB. DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB. DR GO; GO:0016328; C:lateral plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; ISS: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:0071391; P:cellular response to estrogen stimulus; ISS:UniProtKB. DR GO; GO:0048565; P:digestive tract development; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; ISS:UniProtKB. DR GO; GO:0042045; P:epithelial fluid transport; ISS:UniProtKB. DR GO; GO:0048286; P:lung alveolus development; ISS:UniProtKB. DR GO; GO:0045779; P:negative regulation of bone resorption; IEA:Ensembl. DR GO; GO:2001205; P:negative regulation of osteoclast development; IEA:Ensembl. DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISS:UniProtKB. DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0035265; P:organ growth; ISS:UniProtKB. DR GO; GO:0034504; P:protein localization to nucleus; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0120193; P:tight junction organization; ISS:UniProtKB. DR FunFam; 1.20.140.150:FF:000027; Claudin; 1. 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 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; Proteomics identification; Reference proteome; KW Tight junction; Transmembrane; Transmembrane helix. FT CHAIN 1..261 FT /note="Claudin-18" FT /id="PRO_0000144779" 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..174 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 175..195 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 196..261 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 195..261 FT /note="Required for role in regulation of RANKL-induced FT osteoclast differentiation" FT /evidence="ECO:0000250|UniProtKB:P56857" FT REGION 242..261 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 214 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P56857" FT VAR_SEQ 1..69 FT /note="MSTTTCQVVAFLLSILGLAGCIAATGMDMWSTQDLYDNPVTSVFQYEGLWRS FT CVRQSSGFTECRPYFTI -> MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNN FT PVTAVFNYQGLWRSCVRESSGFTECRGYFTL (in isoform A2)" FT /evidence="ECO:0000305" FT /id="VSP_001102" FT VARIANT 149 FT /note="M -> L (in dbSNP:rs17204075)" FT /id="VAR_033775" SQ SEQUENCE 261 AA; 27856 MW; 4362B590D3C2B387 CRC64; MSTTTCQVVA FLLSILGLAG CIAATGMDMW STQDLYDNPV TSVFQYEGLW RSCVRQSSGF TECRPYFTIL GLPAMLQAVR ALMIVGIVLG AIGLLVSIFA LKCIRIGSME DSAKANMTLT SGIMFIVSGL CAIAGVSVFA NMLVTNFWMS TANMYTGMGG MVQTVQTRYT FGAALFVGWV AGGLTLIGGV MMCIACRGLA PEETNYKAVS YHASGHSVAY KPGGFKASTG FGSNTKNKKI YDGGARTEDE VQSYPSKHDY V //