Nomenclature: CD97

Family: Adhesion Class GPCRs

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 835 19p13 CD97 CD97 molecule
Mouse 7 818 8 C2 Cd97 CD97 antigen 9
Rat 7 825 19q11 Cd97 CD97 molecule
Previous and Unofficial Names
TM7LN1
CD97 molecule
CD97 antigen
EGF-TM7 receptor
Leukocyte antigen CD97
seven-span transmembrane protein
seven-transmembrane, heterodimeric receptor associated with inflammation
seven transmembrane helix receptor
Cd97_predicted
LOC361383
CD97 antigen (predicted)
AA409984
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Agonist Comments
Agents tested for their properties as agonists at this receptor include CD55, α5β1 integrin, chrondroitin sulfate B and CD90 (Thy1); however, while each was abel to bind to the receptor as a ligand none were found to have agonist activity at the receptor [16-18,29-30,34,37,44,46].
Primary Transduction Mechanisms
Transducer Effector/Response
G12/G13 family
Comments:  In a ligation-independent manner, CD97 forms heterodimers with and potentiates ligation-dependent signaling of the lysophosphatidic acid (LPA) receptor.
References:  47-48
Tissue Distribution
Hematopoietic stem and progenitor cells and all circulating leukocytes including monocytes, monocyte-derived macrophages, myeloid and plasmacytoid dendritic cells, neutrophilic, eosinophilic and basophilic granulocytes, T, B and NK cells (increased expression on activated lymphocytes)
Species:  Human
Technique:  Flow cytometry
References:  11-12,25-26,32,39
Macrophages, dendritic cells and lymphocytes in most tissues, except microglia
Species:  Human
Technique:  Immunohistochemistry
References:  23,26
Normal (weak expression) and tumorigenic (increased expression) epithelial cells in thyroid, gastrointestinal tract (esophagus, stomach, gall bladder, pancreas, colon)
Species:  Human
Technique:  Immunohistochemistry
References:  1-2,4,8,20-21,23,31,33,38,47,50
Leukocyte infiltrates in eczematous dermatitis, rheumatoid arthritis and other arthritides, multiple sclerosis, psoriasis and atherosclerosis
Species:  Human
Technique:  Immunohistochemistry
References:  15,19,24,39,43-44
Normal and tumorigenic smooth muscle cells in vasculature, urinary bladder, lung bronchi and bronchioles, myometrium and gastrointestinal tract
Species:  Human
Technique:  Immunohistochemistry and immunoprecipitation
References:  5
Gliomas
Species:  Human
Technique:  Microarray analysis and RT-PCR
References:  10
Hematopoietic, epithelial, endothelial, muscle and fat cells in many tissues
Species:  Mouse
Technique:  Immunohistochemistry, LacZ insertion and RT-PCR
References:  35,41
Hematopoietic stem cells and all circulating leukocytes including monocytes, granulocytes, T, B and NK cells
Species:  Mouse
Technique:  Flow cytometry
References:  17,36,40
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Overexpression of CD97 shows increased SRE-luciferase activity
Species:  Human
Tissue:  Transfected Cos7 cells
Response measured:  Gα12/13-mediated RHOA-dependent signaling
References:  48
Physiological Functions
Overexpression facilitates cell adhesion through interaction with CD55 and chondroitin sulfate B
Species:  Human
Tissue:  Fibroblast cell lines
References:  16,18,29-30,37
Overexpression facilitates cell adhesion through interaction with CD55
Species:  Mouse
Tissue:  Fibroblast cell lines
References:  17,34
Overexpression promotes tumor growth in scid mice and enhances single cell motility, proteolytic activity of matrix metalloproteinases and secretion of chemokines
Species:  Human
Tissue:  HT1080 fibrosarcoma cell line
References:  14
Physiological Consequences of Altering Gene Expression
Attenuation of experimental arthritis. Mice with null allele have reduced disease activity in collagen-induced and KRN serum-transfer arthritis
Species:  Mouse
Tissue:  Synovium
Technique:  Gene knockouts
References:  22
Mild granulocytosis, improved anti-bacterial host defense. Mice with null allele have increased granulopoietic activity and are more resistant to Listeria monocytogenes infection
Species:  Mouse
Tissue:  Granulocytes
Technique:  Gene knockouts
References:  41-42,45
Enhanced thyroid cancer progression. Transgenic over-expression in thyroid follicular epithelial cells (thyroglobulin promotor) increases vascular invasion and lung metastasis in a model of thyroid follicular cell carcinogenesis.
Species:  Mouse
Tissue:  Thyroid follicular epithelial cells
Technique:  Gene over-expression
References:  47
Transgenic over-expression in intestinal epithelial cells (villin promotor) strengthens adherens junctions and attenuates DSS-induced colitis
Species:  Mouse
Tissue:  Intestinal epithelial cells
Technique:  Gene over-expression
References:  6
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cd97tm1Kake Cd97tm1Kake/Cd97tm1Kake
B6.129S6-Cd97
MGI:1347095  MP:0002411 decreased susceptibility to bacterial infection PMID: 17158902 
Cd97tm1Kake Cd97tm1Kake/Cd97tm1Kake
B6.129S6-Cd97
MGI:1347095  MP:0009789 decreased susceptibility to bacterial infection induced morbidity/mortality PMID: 17158902 
Cd97tm1Kake Cd97tm1Kake/Cd97tm1Kake
B6.129S6-Cd97
MGI:1347095  MP:0000322 increased granulocyte number PMID: 17158902 
Cd97tm1.1Joha Cd97tm1.1Joha/Cd97tm1.1Joha
involves: 129P2/OlaHsd * C57BL/6J * FVB/N
MGI:1347095  MP:0000322 increased granulocyte number PMID: 18941248 
Cd97tm1Dgen Cd97tm1Dgen/Cd97tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1347095  MP:0002169 no abnormal phenotype detected
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  Full-length isoform with 5 EGF-like domains (EGF1-5), binds chondroitin sulfate B, binds CD55 very weakly
Amino acids:  835
Nucleotide accession: 
Protein accession: 
References:  16,24,29-30,37
Type:  Splice variant
Species:  Human
Description:  Isoform with 4 EGF-like domains (EGF1,2,3,5), binds CD55 weakly, does not bind chondroitin sulfate B
Amino acids:  786
Nucleotide accession: 
Protein accession: 
References:  16,24,29-30,37
Type:  N-glycosylation
Species:  Human
Description:  CD97 without N-glycosylation of the EGF-like domains does not bind CD55
Amino acids:  835
References:  49
Type:  Splice variant
Species:  Mouse
Description:  Full-length isoform with 4 EGF-like domains and a additional sequence of 45 amino acids between EGF domain 2 and 3 (EGF1,2,X,3,4), does not bind CD55
Amino acids:  818
Nucleotide accession: 
Protein accession: 
References:  17,34
Type:  Splice variant
Species:  Mouse
Description:  Isoform with 3 EGF-like domains (EGF1,2,4), binds CD55
Amino acids:  724
Nucleotide accession: 
Protein accession: 
References:  13,34
Type:  Splice variant
Species:  Mouse
Description:  Isoform with 4 EGF-like domains (EGF1,2,3,4), binds CD55
Amino acids:  773
Nucleotide accession: 
Protein accession: 
References:  17,34
Type:  Splice variant
Species:  Human
Description:  Isoform with 3 EGF-like domains (EGF1,2,5), binds CD55, does not bind chondroitin sulfate B
Amino acids:  742
Nucleotide accession: 
Protein accession: 
References:  16,18,24,29-30,37
Biologically Significant Variant Comments
The interaction with CD55 is mediated by the N-terminal EGF-like domains and requires 3 tandemly arranged EGF-like domains; additional EGF-like domains lower the affinity for CD55 [16,30]. The interaction with chondroitin sulfate B is mediated by the 4th EGF-like domain [3]. Lack of N-glycosylation in the EGF domain region prevents CD55 binding in normal smooth muscle cells [5].
General Comments
CD97 is a receptor that belongs to Family II Adhesion-GPCRs together with EMR1-4 [7,27]. The genes of Family II Adhesion-GPCRs are syntenically clustered on human chromosome 19 suggesting the evolution from an ancestral gene through gene duplication and exon shuffling [28].

REFERENCES

1. Aust G. (2010) Adhesion-GPCRS in tumorigenesis. Adv. Exp. Med. Biol.706: 109-20. [PMID:21618830]

2. Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C. (1997) CD97: a dedifferentiation marker in human thyroid carcinomas. Cancer Res.57 (9): 1798-806. [PMID:9135025]

3. Aust G, Hamann J, Schilling N, Wobus M. (2003) Detection of alternatively spliced EMR2 mRNAs in colorectal tumor cell lines but rare expression of the molecule in colorectal adenocarcinomas. Virchows Arch.443 (1): 32-7. [PMID:12761622]

4. Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M. (2002) CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas. Am. J. Clin. Pathol.118 (5): 699-707. [PMID:12428789]

5. Aust G, Wandel E, Boltze C, Sittig D, Schütz A, Horn LC, Wobus M. (2006) Diversity of CD97 in smooth muscle cells. Cell Tissue Res.324 (1): 139-47. [PMID:16408199]

6. Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G. (2010) Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions. PLoS ONE5 (1): e8507. [PMID:20084281]

7. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics84: 23-33. [PMID:15203201]

8. Boltze C, Schneider-Stock R, Aust G, Mawrin C, Dralle H, Roessner A, Hoang-Vu C. (2002) CD97, CD95 and Fas-L clearly discriminate between chronic pancreatitis and pancreatic ductal adenocarcinoma in perioperative evaluation of cryocut sections. Pathol. Int.52 (2): 83-8. [PMID:11940212]

9. Carver EA, Hamann J, Olsen AS, Stubbs L. (1999) Physical mapping of EMR1 and CD97 in human Chromosome 19 and assignment of Cd97 to mouse Chromosome 8 suggest an ancient genomic duplication. Mamm. Genome10 (10): 1039-40. [PMID:10501980]

10. Chidambaram A, Fillmore HL, Van Meter TE, Dumur CI, Broaddus WC. (2012) Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness. J. Neurosurg.116 (4): 843-53. [PMID:22313360]

11. Eichler W, Aust G, Hamann D. (1994) Characterization of an early activation-dependent antigen on lymphocytes defined by the monoclonal antibody BL-Ac(F2). Scand. J. Immunol.39 (1): 111-5. [PMID:8290889]

12. Eichler W, Hamann J, Aust G. (1997) Expression characteristics of the human CD97 antigen. Tissue Antigens50 (5): 429-38. [PMID:9389316]

13. Fitzmaurice CJ, Brown LE, Kronin V, Jackson DC. (2000) The geometry of synthetic peptide-based immunogens affects the efficiency of T cell stimulation by professional antigen-presenting cells. Int. Immunol.12 (4): 527-35. [PMID:10744654]

14. Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G. (2006) Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion. Am. J. Pathol.169 (5): 1802-11. [PMID:17071601]

15. Gray JX, Haino M, Roth MJ, Maguire JE, Jensen PN, Yarme A, Stetler-Stevenson MA, Siebenlist U, Kelly K. (1996) CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. J. Immunol.157 (12): 5438-47. [PMID:8955192]

16. Hamann J, Stortelers C, Kiss-Toth E, Vogel B, Eichler W, van Lier RA. (1998) Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97. Eur. J. Immunol.28 (5): 1701-7. [PMID:9603477]

17. Hamann J, van Zeventer C, Bijl A, Molenaar C, Tesselaar K, van Lier RA. (2000) Molecular cloning and characterization of mouse CD97. Int. Immunol.12 (4): 439-48. [PMID:10744645]

18. Hamann J, Vogel B, van Schijndel GM, van Lier RA. (1996) The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J. Exp. Med.184 (3): 1185-9. [PMID:9064337]

19. Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP. (1999) Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum.42 (4): 650-8. [PMID:10211878]

20. Han SL, Xu C, Wu XL, Li JL, Liu Z, Zeng QQ. (2010) The impact of expressions of CD97 and its ligand CD55 at the invasion front on prognosis of rectal adenocarcinoma. Int J Colorectal Dis25 (6): 695-702. [PMID:20339853]

21. Hoang-Vu C, Bull K, Schwarz I, Krause G, Schmutzler C, Aust G, Köhrle J, Dralle H. (1999) Regulation of CD97 protein in thyroid carcinoma. J. Clin. Endocrinol. Metab.84 (3): 1104-9. [PMID:10084602]

22. Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J. (2010) Deletion of either CD55 or CD97 ameliorates arthritis in mouse models. Arthritis Rheum.62 (4): 1036-42. [PMID:20131275]

23. Jaspars LH, Vos W, Aust G, Van Lier RA, Hamann J. (2001) Tissue distribution of the human CD97 EGF-TM7 receptor. Tissue Antigens57 (4): 325-31. [PMID:11380941]

24. Kop EN, Kwakkenbos MJ, Teske GJ, Kraan MC, Smeets TJ, Stacey M, Lin HH, Tak PP, Hamann J. (2005) Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue. Arthritis Rheum.52 (2): 442-50. [PMID:15693006]

25. Kop EN, Matmati M, Pouwels W, Leclercq G, Tak PP, Hamann J. (2009) Differential expression of CD97 on human lymphocyte subsets and limited effect of CD97 antibodies on allogeneic T-cell stimulation. Immunol. Lett.123 (2): 160-8. [PMID:19428565]

26. Kwakkenbos MJ, Chang GW, Lin HH, Pouwels W, de Jong EC, van Lier RA, Gordon S, Hamann J. (2002) The human EGF-TM7 family member EMR2 is a heterodimeric receptor expressed on myeloid cells. J Leukoc Biol71: 854-862. [PMID:11994511]

27. Kwakkenbos MJ, Kop EN, Stacey M, Matmati M, Gordon S, Lin HH, Hamann J. (2004) The EGF-TM7 family: a postgenomic view. Immunogenetics55 (10): 655-66. [PMID:14647991]

28. Kwakkenbos MJ, Matmati M, Madsen O, Pouwels W, Wang Y, Bontrop RE, Heidt PJ, Hoek RM, Hamann J. (2006) An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2. FASEB J20: 2582-2584. [PMID:17068111]

29. Kwakkenbos MJ, Pouwels W, Matmati M, Stacey M, Lin HH, Gordon S, van Lier RA, Hamann J. (2005) Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. J. Leukoc. Biol.77 (1): 112-9. [PMID:15498814]

30. Lin HH, Stacey M, Saxby C, Knott V, Chaudhry Y, Evans D, Gordon S, McKnight AJ, Handford P, Lea S. (2001) Molecular analysis of the epidermal growth factor-like short consensus repeat domain-mediated protein-protein interactions: dissection of the CD97-CD55 complex. J. Biol. Chem.276 (26): 24160-9. [PMID:11297558]

31. Loberg RD, Wojno KJ, Day LL, Pienta KJ. (2005) Analysis of membrane-bound complement regulatory proteins in prostate cancer. Urology66 (6): 1321-6. [PMID:16360477]

32. Matmati M, Pouwels W, van Bruggen R, Jansen M, Hoek RM, Verhoeven AJ, Hamann J. (2007) The human EGF-TM7 receptor EMR3 is a marker for mature granulocytes. J. Leukoc. Biol.81 (2): 440-8. [PMID:17108056]

33. Mustafa T, Klonisch T, Hombach-Klonisch S, Kehlen A, Schmutzler C, Koehrle J, Gimm O, Dralle H, Hoang-Vu C. (2004) Expression of CD97 and CD55 in human medullary thyroid carcinomas. Int. J. Oncol.24 (2): 285-94. [PMID:14719104]

34. Qian YM, Haino M, Kelly K, Song WC. (1999) Structural characterization of mouse CD97 and study of its specific interaction with the murine decay-accelerating factor (DAF, CD55). Immunology98 (2): 303-11. [PMID:10540231]

35. Regard JB, Sato IT, Coughlin SR. (2008) Anatomical profiling of G protein-coupled receptor expression. Cell135: 561-571. [PMID:18984166]

36. Schebesta A, McManus S, Salvagiotto G, Delogu A, Busslinger GA, Busslinger M. (2007) Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. Immunity27 (1): 49-63. [PMID:17658281]

37. Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD, Hamann J, Gordon S, Lin HH. (2003) The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood102 (8): 2916-24. [PMID:12829604]

38. Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G. (2002) Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues. Am. J. Pathol.161 (5): 1657-67. [PMID:12414513]

39. van Eijk M, Aust G, Brouwer MS, van Meurs M, Voerman JS, Dijke IE, Pouwels W, Sändig I, Wandel E, Aerts JM, Boot RG, Laman JD, Hamann J. (2010) Differential expression of the EGF-TM7 family members CD97 and EMR2 in lipid-laden macrophages in atherosclerosis, multiple sclerosis and Gaucher disease. Immunol. Lett.129 (2): 64-71. [PMID:20167235]

40. van Pel M, Hagoort H, Hamann J, Fibbe WE. (2008) CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells. Haematologica93 (8): 1137-44. [PMID:18603564]

41. Veninga H, Becker S, Hoek RM, Wobus M, Wandel E, van der Kaa J, van der Valk M, de Vos AF, Haase H, Owens B et al.. (2008) Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. J. Immunol.181 (9): 6574-83. [PMID:18941248]

42. Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J. (2011) A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense. PLoS ONE6 (10): e24431. [PMID:21984892]

43. Visser L, de Vos AF, Hamann J, Melief MJ, van Meurs M, van Lier RA, Laman JD, Hintzen RQ. (2002) Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis. J. Neuroimmunol.132 (1-2): 156-63. [PMID:12417446]

44. Wandel E, Saalbach A, Sittig D, Gebhardt C, Aust G. (2012) Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells. J. Immunol.188 (3): 1442-50. [PMID:22210915]

45. Wang T, Tian L, Haino M, Gao JL, Lake R, Ward Y, Wang H, Siebenlist U, Murphy PM, Kelly K. (2007) Improved antibacterial host defense and altered peripheral granulocyte homeostasis in mice lacking the adhesion class G protein receptor CD97. Infect. Immun.75 (3): 1144-53. [PMID:17158902]

46. Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson WG, Kelly K. (2005) CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood105 (7): 2836-44. [PMID:15576472]

47. Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M et al.. (2012) CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene,  [Epub ahead of print]. [PMID:22797060]

48. Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K. (2011) LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res.71 (23): 7301-11. [PMID:21978933]

49. Wobus M, Vogel B, Schmücking E, Hamann J, Aust G. (2004) N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding. Int. J. Cancer112 (5): 815-22. [PMID:15386373]

50. Wu J, Lei L, Wang S, Gu D, Zhang J. (2012) Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma. J. Biomed. Biotechnol.2012: 587672. [PMID:22547928]

To cite this database page, please use the following:

Jörg Hamann, Gabriela Aust, Hsi-Hsien Lin, Martin Stacey, Tom I. Bonner.
Adhesion Class GPCRs: CD97. Last modified on 23/07/2013. Accessed on 23/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=177.

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