CD97

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Adhesion G protein-coupled receptor E5
Protein CD97 PDB 2bo2.png
PDB rendering based on 2bo2.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADGRE5 ; CD97; TM7LN1
External IDs OMIM601211 MGI1347095 HomoloGene8050 IUPHAR: GeneCards: ADGRE5 Gene
RNA expression pattern
PBB GE CD97 202910 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 976 26364
Ensembl ENSG00000123146 ENSMUSG00000002885
UniProt P48960 Q9Z0M6
RefSeq (mRNA) NM_001025160 NM_001163029
RefSeq (protein) NP_001020331 NP_001156501
Location (UCSC) Chr 19:
14.38 – 14.41 Mb
Chr 8:
83.72 – 83.74 Mb
PubMed search [1] [2]

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene.1234 CD97 is a member of the adhesion GPCR family.56 Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.7

CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts.8910111213 In the case of CD97 the N-terminal domains consist of alternatively spliced epidermal growth factor (EGF)-like domains. Alternative splicing has been observed for this gene and three variants have been found.3 The N-terminal fragment of CD97 contains 3-5 EGF-like domains in human and 3-4 EGF-like domains in mice.14

Ligands

Decay accelerating factor (DAF/CD55), a regulatory protein of the complement cascade, interacts with the first and second EGF-like domains of CD97;15 chondroitin sulfate B with the fourth EGF-like domain;16 α5β1 and αvβ3 integrins with an RGD downstream the EGF-like domains;17 and CD90 (Thy-1) with the GAIN domain.18 N-glycosylation of CD97 within the EGF domains is crucial for CD55 binding.19

Signaling

Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.20 Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling.2122 Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive Gi/o protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce [Ca2+] in breast cancer cells.23

Function

In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation.24 Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis.25 Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.26 Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.27 Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.2829

Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis.30 CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis.3132 In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier.33 Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.34

Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling.20 Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.35 CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle.13 In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.17

Clinical significance

CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.36 CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells.37383940414243 In addition, enhanced CD97 expression has been found at the invasion front of tumors,44 suggesting a possible role in tumor migration/invasion,4546 and correlated with a poorer clinical prognosis.4247484950 Interestingly, CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma;51 the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.52

Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.53 Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.54 CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.2255 It has been shown that CD97 regulates localization and degradation of β-catenin.20 GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes.5657 Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.585960 Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.

References

  1. ^ Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM, Hartmann E, Strauss M, van Lier RA (Aug 1995). "Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain". Journal of Immunology 155 (4): 1942–50. PMID 7636245. 
  2. ^ Hamann J, Hartmann E, van Lier RA (Feb 1996). "Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily". Genomics 32 (1): 144–7. doi:10.1006/geno.1996.0092. PMID 8786105. 
  3. ^ a b "Entrez Gene: CD97 CD97 molecule". 
  4. ^ Hamann, J; Aust, G; Araç, D; Engel, FB; Formstone, C; Fredriksson, R; Hall, RA; Harty, BL; Kirchhoff, C; Knapp, B; Krishnan, A; Liebscher, I; Lin, HH; Martinelli, DC; Monk, KR; Peeters, MC; Piao, X; Prömel, S; Schöneberg, T; Schwartz, TW; Singer, K; Stacey, M; Ushkaryov, YA; Vallon, M; Wolfrum, U; Wright, MW; Xu, L; Langenhan, T; Schiöth, HB (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.". Pharmacological reviews 67 (2): 338–67. PMID 25713288. 
  5. ^ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 1-4419-7912-3. 
  6. ^ Langenhan, T; Aust, G; Hamann, J (21 May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage.". Science signaling 6 (276): re3. PMID 23695165. 
  7. ^ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (Mar 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC 3321182. PMID 22333914. 
  8. ^ van Pel M, Hagoort H, Hamann J, Fibbe WE (Aug 2008). "CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells". Haematologica 93 (8): 1137–44. doi:10.3324/haematol.12838. PMID 18603564. 
  9. ^ Eichler W, Hamann J, Aust G (Nov 1997). "Expression characteristics of the human CD97 antigen". Tissue Antigens 50 (5): 429–38. PMID 9389316. 
  10. ^ Jaspars LH, Vos W, Aust G, Van Lier RA, Hamann J (Apr 2001). "Tissue distribution of the human CD97 EGF-TM7 receptor". Tissue Antigens 57 (4): 325–31. PMID 11380941. 
  11. ^ Aust G, Wandel E, Boltze C, Sittig D, Schütz A, Horn LC, Wobus M (Apr 2006). "Diversity of CD97 in smooth muscle cells". Cell and Tissue Research 324 (1): 139–47. doi:10.1007/s00441-005-0103-2. PMID 16408199. 
  12. ^ 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, van der Poll T, van Lier RA, Verbeek JS, Aust G, Hamann J (Nov 2008). "Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration". Journal of Immunology 181 (9): 6574–83. PMID 18941248. 
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  14. ^ Gordon S, Hamann J, Lin HH, Stacey M (Sep 2011). "F4/80 and the related adhesion-GPCRs". European Journal of Immunology 41 (9): 2472–6. doi:10.1002/eji.201141715. PMID 21952799. 
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  18. ^ Wandel E, Saalbach A, Sittig D, Gebhardt C, Aust G (Feb 2012). "Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells". Journal of Immunology 188 (3): 1442–50. doi:10.4049/jimmunol.1003944. PMID 22210915. 
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  20. ^ a b c Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G (13 January 2010). "Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions". PloS One 5 (1): e8507. doi:10.1371/journal.pone.0008507. PMID 20084281. 
  21. ^ Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K (Dec 2011). "LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells". Cancer Research 71 (23): 7301–11. doi:10.1158/0008-5472.CAN-11-2381. PMID 21978933. 
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  23. ^ Park SJ, Lee KP, Kang S, Chung HY, Bae YS, Okajima F, Im DS (Nov 2013). "Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells". Cellular Signalling 25 (11): 2147–54. doi:10.1016/j.cellsig.2013.07.001. PMID 23838008. 
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  27. ^ Veninga H, de Groot DM, McCloskey N, Owens BM, Dessing MC, Verbeek JS, Nourshargh S, van Eenennaam H, Boots AM, Hamann J (Mar 2011). "CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism". Journal of Leukocyte Biology 89 (3): 413–21. doi:10.1189/jlb.0510280. PMID 21169517. 
  28. ^ Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I (Jul 2006). "Costimulation via CD55 on human CD4+ T cells mediated by CD97". Journal of Immunology 177 (2): 1070–7. PMID 16818763. 
  29. ^ Abbott RJ, Spendlove I, Roversi P, Fitzgibbon H, Knott V, Teriete P, McDonnell JM, Handford PA, Lea SM (Jul 2007). "Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55". The Journal of Biological Chemistry 282 (30): 22023–32. doi:10.1074/jbc.M702588200. PMID 17449467. 
  30. ^ Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP (Apr 1999). "Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue". Arthritis and Rheumatism 42 (4): 650–8. doi:10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S. PMID 10211878. 
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  40. ^ Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C (Jan 2005). "Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas". Cancer Epidemiology, Biomarkers & Prevention 14 (1): 108–19. PMID 15668483. 
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  58. ^ Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G (Nov 2002). "Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues". The American Journal of Pathology 161 (5): 1657–67. doi:10.1016/S0002-9440(10)64443-4. PMID 12414513. 
  59. ^ Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C (Jan 2005). "Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas". Cancer Epidemiology, Biomarkers & Prevention 14 (1): 108–19. PMID 15668483. 
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