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ADGRE5 (CD97 molecule)

Written2007-10Gabriela Aust
University of Leipzig, Faculty of Medicine, Research Laboratories, Center of Surgery, Liebigstr. 20, Leipzig, D-04103, Germany

(Note : for Links provided by Atlas : click)


Alias (NCBI)CD97
HGNC Alias symbTM7LN1
HGNC Alias nameleukocyte antigen CD97
 seven-span transmembrane protein
 seven-transmembrane, heterodimeric receptor associated with inflammation
 seven transmembrane helix receptor
HGNC Previous nameCD97
HGNC Previous nameCD97 antigen
 CD97 molecule
LocusID (NCBI) 976
Atlas_Id 996
Location 19p13.12  [Link to chromosome band 19p13]
Location_base_pair Starts at 14381444 and ends at 14408723 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ADGRE5.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADGRE5 (19p13.12)::ATP2A2 (12q24.11)ADGRE5 (19p13.12)::SDC3 (1p35.2)CCDC88B (11q13.1)::ADGRE5 (19p13.12)


  Genomic organization of CD97 (drawn to scale), boxes represent exons.
Description DNA contains 27.322 kb composed of 20 coding exons. Exons 1-2 encode the 5' untranslated region and the signal peptide, exons 3-7 the five EGF domains, exons 8-13 the extracellular stalk, exons 14-18 the seven-span transmembrane (TM7) domains and exons 19-20 the intracellular part and the 3' untranslated region.
Transcription 3247 bp mRNA transcribed in telomeric to centromeric orientation; 2508 bp open reading frame. Human CD97 exists in three isoforms that result from alternative splicing of exons 5 and 6 and thus contain different numbers of EGF domains in the extracellular part of the molecule. The isoforms are designated as CD97(EGF1,2,5), CD97(EGF1,2,3,5) and CD97(EGF1-5) in human.
Pseudogene No pseudogenes reported.


  Structure of CD97. Three isoforms containing 3, 4, or 5 EGF domains exist. N-glycosylation sites in the EGF domains are indicated.
Description CD97 belongs to the B family of G protein-coupled receptors (GCPRs). Subfamily B2 contains cell surface molecules with long extracellular N-termini (LNB-TM7) known also as adhesion class of heptahelical receptors.
CD97 is the founding member of a small subfamily within the adhesion class called EGF-TM7 family. All EGF-TM7 receptors (CD97, EMR1, , EMR3, EMR4) consist of extracellular tandemly arranged EGF domains, a stalk, the seven-span transmembrane (TM7) und a short intracellular part. They are expressed as heterodimers of a non-covalently bound alpha- and beta-chain resulting from intracellular autocatalytic cleavage at a conserved GCPR proteolytic site (GPS). The alpha-chain represents the extracellular region with the varying numbers of EGF domains and the main part of the stalk and the beta-chain consists of the stalk residue, the TM7 and intracellular part.
Three CD97 isoforms containing 3, 4 or 5 EGF domains are described. The mature full length proteins contain either 722, 766 or 815 amino acids (aa). After cleavage the (secretory) alpha-chains contain 420, 464, or 513 aa. The beta-chain theoretically contains 305 aa with a molecular weight of 34.3 kDa. However, immunoprecipitation of the beta-chain yielded a molecular weight of approximately 28 kDa. The discrepancy between the theoretical and actual molecular weight of the beta-chain is not yet clarified.
Depending on the cell type and transformation status of the cell, CD97 is completely or partly N-glycosylated or naked. In normal muscle cells CD97 is not or only slightly N-glycosylated. The molecular weight for the respective naked alpha-chain of the various CD97 isoforms are 45.6, 50.5 and 55.8 kDa. In hematopoetic cells CD97 is N-glycosylated at the EGF domains resulting in molecular weights of 74-78, 80-82, and 86-89 kDa for the alpha-chains of the respective isoform. During tumor transformation CD97 may get N-glycosylated. Although the CD97 stalk contains many Ser or Thr residues the molecule seems not to be O-glycosylated.
Expression Broad, not cell-type specific.
  • Hematopoetic system: strong in peripheral blood myeloid cells and activated lymphocytes, moderately in subsets of tissue-derived leukocytes;
  • Strong in smooth muscle cells (except for arterial vascular smooth muscle cells), skeletal muscle cells (stronger in slow-twitch fibers), heart muscle cells;
  • Fat cells;
  • Low in normal intestinal, thyroidal epithelial cells, moderately in duct cells of the pancreas, parotis gland and in bile duct cells of the liver.
  • Localisation Usually at the cell membrane; soluble CD97 (sCD97) representing the CD97 alpha-chain in body fluids;
    Skeletal muscle cells: at the sarcolemm and intracellularly in the sacroendoplasmatic reticulum (SR).
    Function CD97 has the ability to bind cellular and extracellular matrix ligands. The first two EGF domains of CD97 bind CD55 (decay accelerating factor). The fourth EGF domain of CD97 and thus only the longest CD97 isoform interacts with the glycosaminoglycan chondroitin sulfate B. CD97 binds to alpha5beta1 and alphavbeta3 integrins through interaction with the CD97 stalk region.
  • Hematopoetic cells: Functional studies indicate a role of CD97 in leukocyte trafficking. CD97 antibodies block tissue localization of immune cells in vivo leading to impaired protection against bacteria and amelioration of autoimmune pathology.
  • Tumor cells: In vitro CD97 increases single cell random motility and directed migration and invasion of tumor cells in 2D and 3D matrices. CD97 enhances proteolytic activity of matrix metalloproteinases (MMPs) and secretion of chemokines in an isoform-specific manner. CD97 (EGF 1,2,5) overexpression promotes tumor growth in scid mice.
    The alpha-chain of the longest CD97 (EGF1-5) isoform (sCD97) enhances angiogenesis in in vivo tumor models.
  • Muscle, fat, duct cells: function unknown.
  • Homology H. sapiens: CD97
    P. troglodytes: CD97
    B. taurus: CD97
    S. scrofa: CD97
    C. lupus: CD97
    M. musculus: CD97
    R. norvegicus: CD97
    Exists only in mammals.


    Note unknown

    Implicated in

    Note Note for all tumors:
    Antibodies to various epitopes of CD97 vary strongly in their staining pattern and cross-reactivity to other EGF-TM7 molecules. The first group of monoclonal antibodies, which includes BL-Ac/F2, VIM-3b and CLB-CD97/1, binds to the EGF domains of CD97 (CD97EGF antibodies). These antibodies also detect EMR2, another member of the EGF-TM7 family. In most cases, this cross-reactivity will not influence the results obtained for CD97 staining in tumors since EMR2 is strongly restricted to myeloid cells. CD97 antibodies MEM-180 and CLB-CD97/3 bind to the stalk region of CD97 (CD97stalk) and do not bind EMR2.
    CD97EGF epitope accessibility depends on cell type-specific N-glycosylation (see above). CD97EGF antibodies detect only N-glycosylated CD97. During tumor transformation, not only the CD97 protein expression level but also the degree of CD97 N-glycosylation varies. Thus, the selection of the CD97 antibody strongly influences the result in immunohistological studies focused on the correlation between CD97 and histopathological subtypes, diagnosis, progression, or prognosis of tumors.
    CD97 in tumors is strongly regulated at the post-trancriptional level.
    Entity Thyroid cancer
    Note In normal thyroid tissue, no or low immunoreactivity of CD97 is found. In differentiated follicular thyroid carcinoma or papillary thyroid carcinoma, CD97 expression is also either lacking or low. Most undifferentiated anaplastic carcinomas reveal high CD97 presentation. CD97 is absent or only weakly present in patients with postoperative T1 tumors but increased greatly with the progression to postoperative T4 tumors. Until now, only antibodies against CD97 EGF domains (CD97EGF antibodies, see above) have been used in studies of thyroid carcinomas.
    Prognosis not determined
    Cytogenetics not determined
    Oncogenesis Overexpression of CD97 might be important for the progression of thyroid cancer.
    Entity Colorectal cancer
    Note Normal human colorectal epithelium is slightly CD97-positive. Most colorectal carcinomas express CD97. The strongest staining for CD97 occurs in scattered tumor cells at the invasion front compared to cells located within solid tumor formations of the same tumor. Carcinomas with more strongly CD97-stained scattered tumor cells show a poorer clinical stage as well as increased lymph vessel invasion compared to cases with uniform CD97 staining.
    Prognosis not determined
    Cytogenetics not determined
    Oncogenesis Overexpression of CD97 might be important for invasion and metastasis of colorectal cancer.
    Entity Gastric cancer
    Note CD97 is present in normal parietal cells of gastric mucosa. It is stronger expressed by most gastric carcinomas. Half of the tumors show scattered tumor cells at the invasion front with stronger CD97 expression than tumor cells located in solid tumor formations.
    Prognosis not determined
    Cytogenetics not determined
    Entity Leiomyosarcoma
    Note Normal smooth muscle cells are CD97-positive. In this cell type CD97 is not N-glycosylated. Thus, monoclonal antibodies that detect an N-glycosylation dependent epitop of CD97 do not react with normal smooth muscle cells (CD97EGF antibodies). During transformation CD97 get partly N-glyocosylated in most uterine leiomyoma and or completely N-glyocosylated in nearly 25% of the leiomyosarcomas. These tumors are now positive for CD97EGF antibodies. However, one third of leiomyosarcomas are completely devoid of CD97.
    Prognosis not determined
    Cytogenetics not determined


    CD97: a dedifferentiation marker in human thyroid carcinomas.
    Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C
    Cancer research. 1997 ; 57 (9) : 1798-1806.
    PMID 9135025
    CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas.
    Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M
    American journal of clinical pathology. 2002 ; 118 (5) : 699-707.
    PMID 12428789
    Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion.
    Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G
    The American journal of pathology. 2006 ; 169 (5) : 1802-1811.
    PMID 17071601
    Comparative study of gill neuroepithelial cells and their innervation in teleosts and Xenopus tadpoles.
    Saltys HA, Jonz MG, Nurse CA
    Cell and tissue research. 2006 ; 323 (1) : 1-10.
    PMID 16163489
    Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues.
    Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G
    The American journal of pathology. 2002 ; 161 (5) : 1657-1667.
    PMID 12414513
    CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells.
    Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson WG, Kelly K
    Blood. 2005 ; 105 (7) : 2836-2844.
    PMID 15576472


    This paper should be referenced as such :
    Aust, G
    CD97 (CD97 molecule)
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):201-203.
    Free journal version : [ pdf ]   [ DOI ]

    External links


    HGNC (Hugo)ADGRE5   1711
    Entrez_Gene (NCBI)ADGRE5    adhesion G protein-coupled receptor E5
    AliasesCD97; TM7LN1
    GeneCards (Weizmann)ADGRE5
    Ensembl hg19 (Hinxton)ENSG00000123146 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000123146 [Gene_View]  ENSG00000123146 [Sequence]  chr19:14381444-14408723 [Contig_View]  ADGRE5 [Vega]
    ICGC DataPortalENSG00000123146
    TCGA cBioPortalADGRE5
    AceView (NCBI)ADGRE5
    Genatlas (Paris)ADGRE5
    SOURCE (Princeton)ADGRE5
    Genetics Home Reference (NIH)ADGRE5
    Genomic and cartography
    GoldenPath hg38 (UCSC)ADGRE5  -     chr19:14381444-14408723 +  19p13.12   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)ADGRE5  -     19p13.12   [Description]    (hg19-Feb_2009)
    GoldenPathADGRE5 - 19p13.12 [CytoView hg19]  ADGRE5 - 19p13.12 [CytoView hg38]
    Genome Data Viewer NCBIADGRE5 [Mapview hg19]  
    Gene and transcription
    Genbank (Entrez)AI890331 AK097264 AK225655 AK225677 AK292159
    RefSeq transcript (Entrez)NM_001025160 NM_001784 NM_078481
    Consensus coding sequences : CCDS (NCBI)ADGRE5
    Gene ExpressionADGRE5 [ NCBI-GEO ]   ADGRE5 [ EBI - ARRAY_EXPRESS ]   ADGRE5 [ SEEK ]   ADGRE5 [ MEM ]
    Gene Expression Viewer (FireBrowse)ADGRE5 [ Firebrowse - Broad ]
    GenevisibleExpression of ADGRE5 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)976
    GTEX Portal (Tissue expression)ADGRE5
    Human Protein AtlasENSG00000123146-ADGRE5 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP48960   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP48960  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP48960
    Domaine pattern : Prosite (Expaxy)ASX_HYDROXYL (PS00010)    EGF_3 (PS50026)    EGF_CA (PS01187)    G_PROTEIN_RECEP_F2_2 (PS00650)    G_PROTEIN_RECEP_F2_4 (PS50261)    GPS (PS50221)   
    Domains : Interpro (EBI)EGF-like_Ca-bd_dom    EGF-like_dom    EGF-type_Asp/Asn_hydroxyl_site    EGF_Ca-bd_CS    GPCR_2-like    GPCR_2_ADGRE2_ADGRE5    GPCR_2_secretin-like    GPCR_2_secretin-like_CS    GPS    Growth_fac_rcpt_cys_sf   
    Domain families : Pfam (Sanger)7tm_2 (PF00002)    EGF_CA (PF07645)    GPS (PF01825)   
    Domain families : Pfam (NCBI)pfam00002    pfam07645    pfam01825   
    Domain families : Smart (EMBL)EGF (SM00181)  EGF_CA (SM00179)  GPS (SM00303)  
    Conserved Domain (NCBI)ADGRE5
    PDB (RSDB)2BOU   
    PDB Europe2BOU   
    PDB (PDBSum)2BOU   
    PDB (IMB)2BOU   
    Structural Biology KnowledgeBase2BOU   
    SCOP (Structural Classification of Proteins)2BOU   
    CATH (Classification of proteins structures)2BOU   
    AlphaFold pdb e-kbP48960   
    Human Protein Atlas [tissue]ENSG00000123146-ADGRE5 [tissue]
    Protein Interaction databases
    DIP (DOE-UCLA)P48960
    IntAct (EBI)P48960
    Ontologies - Pathways
    Ontology : AmiGOtransmembrane signaling receptor activity  G protein-coupled receptor activity  calcium ion binding  protein binding  plasma membrane  integral component of plasma membrane  focal adhesion  inflammatory response  immune response  cell adhesion  cell surface receptor signaling pathway  G protein-coupled receptor signaling pathway  adenylate cyclase-activating G protein-coupled receptor signaling pathway  cell-cell signaling  membrane  secretory granule membrane  neutrophil degranulation  extracellular exosome  
    Ontology : EGO-EBItransmembrane signaling receptor activity  G protein-coupled receptor activity  calcium ion binding  protein binding  plasma membrane  integral component of plasma membrane  focal adhesion  inflammatory response  immune response  cell adhesion  cell surface receptor signaling pathway  G protein-coupled receptor signaling pathway  adenylate cyclase-activating G protein-coupled receptor signaling pathway  cell-cell signaling  membrane  secretory granule membrane  neutrophil degranulation  extracellular exosome  
    NDEx NetworkADGRE5
    Atlas of Cancer Signalling NetworkADGRE5
    Wikipedia pathwaysADGRE5
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000123146
    Phylogenetic Trees/Animal Genes : TreeFamADGRE5
    Homologs : HomoloGeneADGRE5
    Homology/Alignments : Family Browser (UCSC)ADGRE5
    Gene fusions - Rearrangements
    Fusion : QuiverADGRE5
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerADGRE5 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)ADGRE5
    Exome Variant ServerADGRE5
    GNOMAD BrowserENSG00000123146
    Varsome BrowserADGRE5
    ACMGADGRE5 variants
    Genomic Variants (DGV)ADGRE5 [DGVbeta]
    DECIPHERADGRE5 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisADGRE5 
    ICGC Data PortalADGRE5 
    TCGA Data PortalADGRE5 
    Broad Tumor PortalADGRE5
    OASIS PortalADGRE5 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICADGRE5  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DADGRE5
    Mutations and Diseases : HGMDADGRE5
    LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
    DgiDB (Drug Gene Interaction Database)ADGRE5
    DoCM (Curated mutations)ADGRE5
    CIViC (Clinical Interpretations of Variants in Cancer)ADGRE5
    NCG (London)ADGRE5
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Genetic Testing Registry ADGRE5
    NextProtP48960 [Medical]
    Target ValidationADGRE5
    Huge Navigator ADGRE5 [HugePedia]
    Clinical trials, drugs, therapy
    Protein Interactions : CTDADGRE5
    Pharm GKB GenePA26248
    Clinical trialADGRE5
    canSAR (ICR)ADGRE5
    DataMed IndexADGRE5
    Other databaseFamily 2 or B of the G-protein-coupled receptors (GCPRs)
    PubMed85 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Fri Oct 8 21:14:32 CEST 2021

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