CD97

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene.[5][6][7][8] CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family.[9][10] 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.[11]

ADGRE5
Identifiers
AliasesADGRE5, TM7LN1, CD97, adhesion G protein-coupled receptor E5
External IDsOMIM: 601211 MGI: 1347095 HomoloGene: 8050 GeneCards: ADGRE5
Gene location (Human)
Chr.Chromosome 19 (human)[1]
Band19p13.12Start14,380,501 bp[1]
End14,408,725 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

976

26364

Ensembl

ENSG00000123146

ENSMUSG00000002885

UniProt

P48960

Q9Z0M6

RefSeq (mRNA)

NM_001025160
NM_001784
NM_078481

NM_001163029
NM_001163030
NM_001163031
NM_011925

RefSeq (protein)

NP_001020331
NP_001775
NP_510966

NP_001156501
NP_001156502
NP_001156503
NP_036055

Location (UCSC)Chr 19: 14.38 – 14.41 MbChr 8: 83.72 – 83.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts.[12][13][14][15][16][17] 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.[7] The N-terminal fragment of CD97 contains 3-5 EGF-like domains in human and 3-4 EGF-like domains in mice.[18]

Ligands

Decay accelerating factor (DAF/CD55), a regulatory protein of the complement cascade, interacts with the first and second EGF-like domains of CD97;[19] chondroitin sulfate B with the fourth EGF-like domain;[20] α5β1 and αvβ3 integrins with an RGD downstream the EGF-like domains;[21] and CD90 (Thy-1) with the GAIN domain.[22] N-glycosylation of CD97 within the EGF domains is crucial for CD55 binding.[23]

Signaling

Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.[24] 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.[25][26] 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.[27]

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.[28] 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.[29] Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.[30] Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.[31] Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.[32][33]

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.[34] 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.[35][36] 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.[37] 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.[24] Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.[38] 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.[17] In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.[21]

Clinical significance

CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.[39] 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.[39][40][41][42][43][44][45] In addition, enhanced CD97 expression has been found at the invasion front of tumors,[46] suggesting a possible role in tumor migration/invasion,[43][46] and correlated with a poorer clinical prognosis.[44][41][42][47][48] 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;[49] the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.[50]

Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.[51] Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.[52] CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.[26][25] It has been shown that CD97 regulates localization and degradation of β-catenin.[24] 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.[53][54] 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.[41][42][55] Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.

References

  1. GRCh38: Ensembl release 89: ENSG00000123146 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000002885 - Ensembl, May 2017
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  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. 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.
  7. "Entrez Gene: CD97 CD97 molecule".
  8. 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. doi:10.1124/pr.114.009647. PMC 4394687. PMID 25713288.
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