Biology:CD97

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[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.[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.

References

  1. ↑ "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. doi:10.4049/jimmunol.155.4.1942. PMID 7636245. 
  2. ↑ "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. doi:10.1006/geno.1996.0092. PMID 8786105. 
  3. ↑ 3.0 3.1 "Entrez Gene: CD97 CD97 molecule". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=976. 
  4. ↑ Hamann, J; Aust, G; Araç, D; Engel, FB; Formstone, C; Fredriksson, R; Hall, RA; Harty, BL et al. (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.". Pharmacological Reviews 67 (2): 338–67. doi:10.1124/pr.114.009647. PMID 25713288. 
  5. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 978-1-4419-7912-4. 
  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. doi:10.1126/scisignal.2003825. PMID 23695165. 
  7. ↑ "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal 31 (6): 1364–78. Mar 2012. doi:10.1038/emboj.2012.26. PMID 22333914. 
  8. ↑ "CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells". Haematologica 93 (8): 1137–44. Aug 2008. doi:10.3324/haematol.12838. PMID 18603564. 
  9. ↑ "Expression characteristics of the human CD97 antigen". Tissue Antigens 50 (5): 429–38. Nov 1997. doi:10.1111/j.1399-0039.1997.tb02897.x. PMID 9389316. 
  10. ↑ "Tissue distribution of the human CD97 EGF-TM7 receptor". Tissue Antigens 57 (4): 325–31. Apr 2001. doi:10.1034/j.1399-0039.2001.057004325.x. PMID 11380941. 
  11. ↑ "Diversity of CD97 in smooth muscle cells". Cell and Tissue Research 324 (1): 139–47. Apr 2006. doi:10.1007/s00441-005-0103-2. PMID 16408199. 
  12. ↑ "Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration". Journal of Immunology 181 (9): 6574–83. Nov 2008. doi:10.4049/jimmunol.181.9.6574. PMID 18941248. 
  13. ↑ 13.0 13.1 "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. doi:10.1371/journal.pone.0100513. PMID 24949957. Bibcode: 2014PLoSO...9j0513Z. 
  14. ↑ "F4/80 and the related adhesion-GPCRs". European Journal of Immunology 41 (9): 2472–6. Sep 2011. doi:10.1002/eji.201141715. PMID 21952799. 
  15. ↑ "Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97". European Journal of Immunology 28 (5): 1701–7. May 1998. doi:10.1002/(SICI)1521-4141(199805)28:05<1701::AID-IMMU1701>3.0.CO;2-2. PMID 9603477. 
  16. ↑ "The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF)". The Journal of Experimental Medicine 184 (3): 1185–9. Sep 1996. doi:10.1084/jem.184.3.1185. PMID 9064337. 
  17. ↑ 17.0 17.1 "CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells". Blood 105 (7): 2836–44. Apr 2005. doi:10.1182/blood-2004-07-2878. PMID 15576472. 
  18. ↑ "Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells". Journal of Immunology 188 (3): 1442–50. Feb 2012. doi:10.4049/jimmunol.1003944. PMID 22210915. 
  19. ↑ "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. doi:10.1002/ijc.20483. PMID 15386373. 
  20. ↑ 20.0 20.1 20.2 "Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions". PLOS ONE 5 (1): e8507. 13 January 2010. doi:10.1371/journal.pone.0008507. PMID 20084281. Bibcode: 2010PLoSO...5.8507B. 
  21. ↑ 21.0 21.1 "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. doi:10.1158/0008-5472.CAN-11-2381. PMID 21978933. 
  22. ↑ 22.0 22.1 "CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model". Oncogene 32 (22): 2726–38. May 2013. doi:10.1038/onc.2012.301. PMID 22797060. 
  23. ↑ "Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells". Cellular Signalling 25 (11): 2147–54. Nov 2013. doi:10.1016/j.cellsig.2013.07.001. PMID 23838008. 
  24. ↑ "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. doi:10.4049/jimmunol.172.2.1125. PMID 14707087. 
  25. ↑ "A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense". PLOS ONE 6 (10): e24431. 2011. doi:10.1371/journal.pone.0024431. PMID 21984892. Bibcode: 2011PLoSO...624431V. 
  26. ↑ "CD97 in Leukocyte Trafficking". Adhesion-GPCRS. Advances in Experimental Medicine and Biology. 706. Springer. 2010. pp. 128–37. doi:10.1007/978-1-4419-7913-1_11. ISBN 978-1-4419-7912-4. https://pure.rug.nl/ws/files/243059903/CD97_in_Leukocyte_Trafficking.pdf. 
  27. ↑ "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. doi:10.1189/jlb.0510280. PMID 21169517. 
  28. ↑ "Costimulation via CD55 on human CD4+ T cells mediated by CD97". Journal of Immunology 177 (2): 1070–7. Jul 2006. doi:10.4049/jimmunol.177.2.1070. PMID 16818763. 
  29. ↑ "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. doi:10.1074/jbc.M702588200. PMID 17449467. 
  30. ↑ 30.0 30.1 "Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue". Arthritis and Rheumatism 42 (4): 650–8. Apr 1999. doi:10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S. PMID 10211878. 
  31. ↑ "CD97 neutralisation increases resistance to collagen-induced arthritis in mice". Arthritis Research & Therapy 8 (5): R155. 2006. doi:10.1186/ar2049. PMID 17007638. 
  32. ↑ "Deletion of either CD55 or CD97 ameliorates arthritis in mouse models". Arthritis and Rheumatism 62 (4): 1036–42. Apr 2010. doi:10.1002/art.27347. PMID 20131275. 
  33. ↑ "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. doi:10.1016/s0165-5728(02)00306-5. PMID 12417446. https://research.rug.nl/en/publications/f9232099-1115-42a4-b3d1-e856ea2165f4. 
  34. ↑ "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. doi:10.1016/j.febslet.2010.12.005. PMID 21156175. 
  35. ↑ 35.0 35.1 "CD97: a dedifferentiation marker in human thyroid carcinomas". Cancer Research 57 (9): 1798–806. May 1997. PMID 9135025. 
  36. ↑ "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. doi:10.1309/A6AB-VF3F-7M88-C0EJ. PMID 12428789. 
  37. ↑ 37.0 37.1 37.2 "Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues". The American Journal of Pathology 161 (5): 1657–67. Nov 2002. doi:10.1016/S0002-9440(10)64443-4. PMID 12414513. 
  38. ↑ 38.0 38.1 38.2 "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. doi:10.1158/1055-9965.108.14.1. PMID 15668483. 
  39. ↑ 39.0 39.1 "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. doi:10.1371/journal.pone.0062765. PMID 23658650. Bibcode: 2013PLoSO...862765S. 
  40. ↑ 40.0 40.1 "Phage display discovery of novel molecular targets in glioblastoma-initiating cells". Cell Death and Differentiation 21 (8): 1325–39. Aug 2014. doi:10.1038/cdd.2014.65. PMID 24832468. 
  41. ↑ "Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells". PLOS ONE 10 (2): e0111532. 2015. doi:10.1371/journal.pone.0111532. PMID 25714433. Bibcode: 2015PLoSO..1011532S. 
  42. ↑ 42.0 42.1 "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. doi:10.1002/mc.20262. PMID 16929497. 
  43. ↑ "Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma". Journal of Biomedicine & Biotechnology 2012: 587672. 2012. doi:10.1155/2012/587672. PMID 22547928. 
  44. ↑ "Expression and prognostic value of CD97 and its ligand CD55 in pancreatic cancer". Oncology Letters 9 (2): 793–797. Feb 2015. doi:10.3892/ol.2014.2751. PMID 25624904. 
  45. ↑ "The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma". PLOS ONE 7 (6): e39989. 2012. doi:10.1371/journal.pone.0039989. PMID 22768192. Bibcode: 2012PLoSO...739989L. 
  46. ↑ "Role of CD97 isoforms in gastric carcinoma". International Journal of Oncology 36 (6): 1401–8. Jun 2010. doi:10.3892/ijo_00000625. PMID 20428763. 
  47. ↑ "Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion". The American Journal of Pathology 169 (5): 1802–11. Nov 2006. doi:10.2353/ajpath.2006.060006. PMID 17071601. 
  48. ↑ "Prometastatic GPCR CD97 is a direct target of tumor suppressor microRNA-126". ACS Chemical Biology 9 (2): 334–8. Feb 2014. doi:10.1021/cb400704n. PMID 24274104. 
  49. ↑ "Beta-catenin--a linchpin in colorectal carcinogenesis?". The American Journal of Pathology 160 (2): 389–401. Feb 2002. doi:10.1016/s0002-9440(10)64856-0. PMID 11839557. 
  50. ↑ "GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy". Cellular Signalling 20 (4): 581–9. Apr 2008. doi:10.1016/j.cellsig.2007.10.018. PMID 18023328. 
  51. ↑ "Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines". Thyroid 15 (3): 222–31. Mar 2005. doi:10.1089/thy.2005.15.222. PMID 15785241. 

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