CD97 explained

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene.[1] [2] [3] [4] CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family.[5] [6] 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.[8] [9] [10] [11] [12] [13] 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. 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.[21] [22] 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.[28] [29]

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.[31] [32] 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.[30]

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.[34] 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.[35] 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.[35] [36] [37] [38] [39] [40] [41] In addition, enhanced CD97 expression has been found at the invasion front of tumors,[42] suggesting a possible role in tumor migration/invasion,[39] [42] and correlated with a poorer clinical prognosis.[40] [37] [38] [43] [44] 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;[45] the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.[46]

Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.[47] Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.[48] CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.[22] [21] 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.[49] [50] 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.[37] [38] [51] Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.

External links

Notes and References

  1. Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM, Hartmann E, Strauss M, van Lier RA . 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 . Aug 1995 . 10.4049/jimmunol.155.4.1942 . 7636245 . 10538838 . free .
  2. Hamann J, Hartmann E, van Lier RA . 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 . Feb 1996 . 8786105 . 10.1006/geno.1996.0092 .
  3. Web site: 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 . International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors . Pharmacological Reviews . 67 . 2 . 338–367 . April 2015 . 25713288 . 4394687 . 10.1124/pr.114.009647 .
  5. Book: Stacey M, Yona S . Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology) . Springer . Berlin . 2011 . 978-1-4419-7912-4 .
  6. Langenhan T, Aust G, Hamann J . Sticky signaling--adhesion class G protein-coupled receptors take the stage . Science Signaling . 6 . 276 . re3 . May 2013 . 23695165 . 10.1126/scisignal.2003825 . 6958640 .
  7. Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT . A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis . The EMBO Journal . 31 . 6 . 1364–78 . Mar 2012 . 22333914 . 3321182 . 10.1038/emboj.2012.26 .
  8. van Pel M, Hagoort H, Hamann J, Fibbe WE . CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells . Haematologica . 93 . 8 . 1137–44 . Aug 2008 . 18603564 . 10.3324/haematol.12838 . free .
  9. Eichler W, Hamann J, Aust G . Expression characteristics of the human CD97 antigen . Tissue Antigens . 50 . 5 . 429–38 . Nov 1997 . 9389316 . 10.1111/j.1399-0039.1997.tb02897.x.
  10. Jaspars LH, Vos W, Aust G, Van Lier RA, Hamann J . Tissue distribution of the human CD97 EGF-TM7 receptor . Tissue Antigens . 57 . 4 . 325–31 . Apr 2001 . 11380941 . 10.1034/j.1399-0039.2001.057004325.x. free .
  11. Aust G, Wandel E, Boltze C, Sittig D, Schütz A, Horn LC, Wobus M . Diversity of CD97 in smooth muscle cells . Cell and Tissue Research . 324 . 1 . 139–47 . Apr 2006 . 16408199 . 10.1007/s00441-005-0103-2 . 36161414 .
  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 . Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration . Journal of Immunology . 181 . 9 . 6574–83 . Nov 2008 . 18941248 . 10.4049/jimmunol.181.9.6574. free .
  13. Zyryanova T, Schneider R, Adams V, Sittig D, Kerner C, Gebhardt C, Ruffert H, Glasmacher S, Hepp P, Punkt K, Neuhaus J, Hamann J, Aust G . Skeletal muscle expression of the adhesion-GPCR CD97: CD97 deletion induces an abnormal structure of the sarcoplasmatic reticulum but does not impair skeletal muscle function . PLOS ONE . 9 . 6 . e100513 . 2014 . 24949957 . 10.1371/journal.pone.0100513 . 4065095. 2014PLoSO...9j0513Z . free .
  14. Gordon S, Hamann J, Lin HH, Stacey M . F4/80 and the related adhesion-GPCRs . European Journal of Immunology . 41 . 9 . 2472–6 . Sep 2011 . 21952799 . 10.1002/eji.201141715 . free .
  15. Hamann J, Stortelers C, Kiss-Toth E, Vogel B, Eichler W, van Lier RA . Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97 . European Journal of Immunology . 28 . 5 . 1701–7 . May 1998 . 9603477 . 10.1002/(SICI)1521-4141(199805)28:05<1701::AID-IMMU1701>3.0.CO;2-2 . 21654966 . free .
  16. Hamann J, Vogel B, van Schijndel GM, van Lier RA . The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF) . The Journal of Experimental Medicine . 184 . 3 . 1185–9 . Sep 1996 . 9064337 . 10.1084/jem.184.3.1185 . 2192782.
  17. Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson WG, Kelly K . CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells . Blood . 105 . 7 . 2836–44 . Apr 2005 . 15576472 . 10.1182/blood-2004-07-2878 . free .
  18. Wandel E, Saalbach A, Sittig D, Gebhardt C, Aust G . Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells . Journal of Immunology . 188 . 3 . 1442–50 . Feb 2012 . 22210915 . 10.4049/jimmunol.1003944 . free .
  19. Wobus M, Vogel B, Schmücking E, Hamann J, Aust G . N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding . International Journal of Cancer . 112 . 5 . 815–22 . Dec 2004 . 15386373 . 10.1002/ijc.20483 . 25515098 .
  20. Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G . Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions . PLOS ONE . 5 . 1 . e8507 . 13 January 2010 . 20084281 . 10.1371/journal.pone.0008507 . 2801611. 2010PLoSO...5.8507B . free .
  21. Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K . LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells . Cancer Research . 71 . 23 . 7301–11 . Dec 2011 . 21978933 . 10.1158/0008-5472.CAN-11-2381 . 6697138 . free .
  22. Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M, Garcia-Rostan G, Kelly K . CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model . Oncogene . 32 . 22 . 2726–38 . May 2013 . 22797060 . 10.1038/onc.2012.301 . 7561260 . 10261/116503 . free .
  23. Park SJ, Lee KP, Kang S, Chung HY, Bae YS, Okajima F, Im DS . Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells . Cellular Signalling . 25 . 11 . 2147–54 . Nov 2013 . 23838008 . 10.1016/j.cellsig.2013.07.001 .
  24. Leemans JC, te Velde AA, Florquin S, Bennink RJ, de Bruin K, van Lier RA, van der Poll T, Hamann J . The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense . Journal of Immunology . 172 . 2 . 1125–31 . Jan 2004 . 14707087 . 10.4049/jimmunol.172.2.1125. free .
  25. Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J . A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense . PLOS ONE . 6 . 10 . e24431 . 2011 . 21984892 . 10.1371/journal.pone.0024431 . 3184942. 2011PLoSO...624431V . free .
  26. Book: Hamann J, Veninga H, de Groot DM, Visser L, Hofstra CL, Tak PP, Laman JD, Boots AM, van Eenennaam H . CD97 in Leukocyte Trafficking . Advances in Experimental Medicine and Biology . Adhesion-GPCRS . 706 . 128–37 . 2010 . Springer . 21618832 . 10.1007/978-1-4419-7913-1_11 . 978-1-4419-7912-4 . https://pure.rug.nl/ws/files/243059903/CD97_in_Leukocyte_Trafficking.pdf .
  27. Veninga H, de Groot DM, McCloskey N, Owens BM, Dessing MC, Verbeek JS, Nourshargh S, van Eenennaam H, Boots AM, Hamann J . 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 . Mar 2011 . 21169517 . 10.1189/jlb.0510280 . 21436547 .
  28. Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I . Costimulation via CD55 on human CD4+ T cells mediated by CD97 . Journal of Immunology . 177 . 2 . 1070–7 . Jul 2006 . 16818763 . 10.4049/jimmunol.177.2.1070. free .
  29. Abbott RJ, Spendlove I, Roversi P, Fitzgibbon H, Knott V, Teriete P, McDonnell JM, Handford PA, Lea SM . 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 . Jul 2007 . 17449467 . 10.1074/jbc.M702588200 . free .
  30. Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP . Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue . Arthritis and Rheumatism . 42 . 4 . 650–8 . Apr 1999 . 10211878 . 10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S .
  31. Kop EN, Adriaansen J, Smeets TJ, Vervoordeldonk MJ, van Lier RA, Hamann J, Tak PP . CD97 neutralisation increases resistance to collagen-induced arthritis in mice . . 8 . 5 . R155 . 2006 . 17007638 . 10.1186/ar2049 . 1779430 . free .
  32. Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J . Deletion of either CD55 or CD97 ameliorates arthritis in mouse models . Arthritis and Rheumatism . 62 . 4 . 1036–42 . Apr 2010 . 20131275 . 10.1002/art.27347 .
  33. Visser L, de Vos AF, Hamann J, Melief MJ, van Meurs M, van Lier RA, Laman JD, Hintzen RQ . Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis . Journal of Neuroimmunology . 132 . 1–2 . 156–63 . Nov 2002 . 12417446 . 10.1016/s0165-5728(02)00306-5. 23377628 .
  34. Hsiao CC, Chen HY, Chang GW, Lin HH . GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation . FEBS Letters . 585 . 2 . 313–8 . Jan 2011 . 21156175 . 10.1016/j.febslet.2010.12.005 . 24457862 . free .
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  36. Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M . CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas . American Journal of Clinical Pathology . 118 . 5 . 699–707 . Nov 2002 . 12428789 . 10.1309/A6AB-VF3F-7M88-C0EJ . free .
  37. Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G . Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues . The American Journal of Pathology . 161 . 5 . 1657–67 . Nov 2002 . 12414513 . 10.1016/S0002-9440(10)64443-4 . 1850798.
  38. 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 . 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 . Jan 2005 . 10.1158/1055-9965.108.14.1 . 15668483 . 23543805 . free .
  39. Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O, Kaur G, Sun MZ, Kim JM, Oh T, Berger MS, Parsa AT . Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients . PLOS ONE . 8 . 4 . e62765 . 2013 . 23658650 . 10.1371/journal.pone.0062765 . 3637305. 2013PLoSO...862765S . free .
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  42. Wobus M, Huber O, Hamann J, Aust G . CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway . Molecular Carcinogenesis . 45 . 11 . 881–6 . Nov 2006 . 16929497 . 10.1002/mc.20262 . 24924901 .
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