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TNFRSF9 (TNF receptor superfamily member 9)

Written2019-01Anette Gjörloff Wingren and Barnabas Nyesiga
Biomedical science, Health and society, Malmö University, Malmö, Sweden nyesigabarnabas@gmail.com; anette.gjorloff-wingren@mah.se

Abstract Review on TNFRSF9 (CD137), with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords TNFRSF9; CD137; tumor necrosis factor receptors; Immune response; T cell response.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesILA
tumor necrosis factor receptor superfamily
Alias_symbol (synonym)CD137
4-1BB
Other aliasT-Cell Antigen 4-1BB Homolog 
4-1BB Ligand Receptor 
CD137 Antigen 
CDw137 
CD137 
ILA 
Interleukin-Activated Receptor, Homolog Of Mouse Ly63
Tumor Necrosis Factor Receptor Superfamily, Member 9
HGNC (Hugo) TNFRSF9
LocusID (NCBI) 3604
Atlas_Id 42631
Location 1p36.23  [Link to chromosome band 1p36]
Location_base_pair Starts at 7915871 and ends at 7943165 bp from pter ( according to hg19-Feb_2009)  [Mapping TNFRSF9.png]
 
  Figure 1. Mapping of CD137 gene on chromosome1p36 (from GeneCards CD137 gene).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description CD137 is a member of the tumor necrosis factor receptor superfamily 9 (TNFRSF9) first identified in mice (Kwon 1989, Kwon 1994) and found to map to murine chromosome 4 at the 75.5 cM position. Schwarz et al. isolated a 1.4-kb full-length cDNA from a library constructed from activated human T-cell leukemia virus (HTLV) type 1-transformed human T-lymphocytes (Schwarz 1993). Schwarz et al. localized the CD137 gene to chromosome 1p36, a region that also harbors genes of several other members of this receptor family (e.g., TNFRSF1B (TNFR2), TNFRSF8 (CD30), TNFRSF4 (OX40) and TNFRSF25 (Apo3)) and is associated with deletions and rearrangements in several malignancies including neuroblastomas, myelodysplastic syndrome, and refractory acute non-lymphocytic leukemia (Schwarz 1997).
Human CD137 gene
Human CD137 consists of 255 amino acids with two potential N-linked glycosylation sites (Alderson 1994). Hydrophobicity analysis revealed amino acids 1-17 to be a putative signal peptide followed by an extracellular domain of 169 amino acids and then a transmembrane domain of 27 amino acids between positions 187-213 and lastly a short intracellular domain of 42 amino acids (Alderson 1994). The molecular weight of the protein was calculated to be 27 kDa (Zhou 1995) and was shown to be 60% identical to murine CD137 (Alderson 1994). Five regions of amino acid sequences were conserved between mice and human in the cytoplasmic domain an indication that these residues might be important for CD137 function (Alderson 1994). Murine and human CD137 ligands were identified and cloned by Alderson et al.(Alderson 1994). The human TNFSF9 (CD137L) consisted of 254 amino acids and its gene maps to chromosome 19 in the region 19p13.3 (Alderson 1994). The human CD137-L shows 36% amino acid identity with its murine counterpart (Alderson 1994). High-affinity binding of huCD137 Fc to either native or recombinant human CD137-L was also demonstrated (Alderson 1994). The murine CD137 ligand consists of 309 amino acid polypeptide and its gene maps to murine chromosome 17 (Goodwin 1993).
Mouse CD137 gene
The CD137 gene in mice spans approximately 13kb and consists of 10 exons, two of them in the 50 untranslated regions and eight in the coding region (Kwon 1994). Nucleotide sequence analysis of CD137 showed a single open reading frame, which codes for a polypeptide 256 amino acids in length with a calculated molecular mass of 27.5kDa (Kwon 1994). The first 23 amino acids were shown to be a signal peptide, followed by a cysteine-rich region, which comprised of four potential TNFR motifs, of which the first was partial and the third distinct from those of the TNFR (Kwon 1994). Almost 30% of the amino acids residing between residues 140-185, a part that follows the ligand binding domain, were serine or threonines. These provide a potential site for O-linked glycosylation while amino acids 186-211 form the hydrophobic transmembrane domain which is followed by the stop-transfer sequence containing several basic residues (Kwon 1994).The carboxyl terminal part of the cytoplasmic domain contains two short runs of three and four acidic residues, respectively, and a sequence of five glycines followed by a tyrosine (Kwon 1994).
Transcription CD137 was found to be induced on CD4+ and CD8+ T cells in mice and humans (Kwon 1989, Schwarz 1995, Vinay 1998, Pollok 1993). In mice, the expression takes several hours after stimulation, increases slowly, culminates at 60 hours and declines again by 110 hours (Goodwin 1993, Vinay 1998, Pollok1994). In humans, CD137 mRNA was detected 1.5 hours after stimulation on T lymphocytes, reaching maximal levels at 8 hours, and declining to background levels by 48 hours (Schwarz 1995).

Protein

Description CD137 is a 30-kDa glycoprotein and exists as both a monomer and a 55-kDa dimer on the T cell surface (Kwon 1994).The CD137 gene encodes a 255-amino acid protein with 3 cysteine-rich motifs in the extracellular domain, a transmembrane region, and a short N-terminal cytoplasmic portion containing potential phosphorylation sites (Schwarz 1993).
Structure: Bitra et al.determined the crystal structure of mCD137 to 2.2 Å resolution and found that similar to other TNFRSFs, mCD137 has four cysteine rich domains (CRDs). However, the organization of CRD1 and the orientation of CRD3 and CRD4 with respect to CRD2 in the mCD137 structure distinctly differed from those of other TNFRSFs (Bitra 2017).
Expression In humans, CD137 expression has been reported in follicular DCs (Lindstedt 2003), monocytes (Kienzle 2000), hepatoma cells (Schwarz 1995) and blood vessels from individuals with malignant tumors (Broll 2001). Expression of CD137 soluble form has been reported in the serum of patients with rheumatoid arthritis (Michel 1998). Incresed expression of CD137 in human peripheral blood mononuclear cells post exposure to mitomycin and other DNA damaging agents, such as doxorubicin, bleomycin and girradiation (Kim 2002). Expression of CD137L was observed following stimulation of professional antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages as well as activated B cells in both human and mice (Alderson 1994, Goodwin 1993, Pollok 1994, Futagawa 2002, DeBenedette 1997). CD137 is also expressed by follicular DC, monocytes, mast cells, granulocytes, and endothelial cells (Anderson 2012). Anderson et al. described CD137 protein expression by follicular DC in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 expression was also observed on activated natural killer (NK) (Malero 1998), dendritic cells (DC)(Futagawa 2002) as well as neutrophils (Heinisch 2000 ) in mice.
Localisation Using immunohistochemical studies on human tissue samples to determine in vivo CD137 expression in non-immune tissue samples, Broll et al. found a strong CD137 expression in blood vessel walls, on the endothelial layer, and on the vascular smooth muscle cells.
Function The CD137L-CD137 pathway is known to co-stimulate T cells to carry out effector functions such as eradication of established tumors (Melero 1997, Ye 2002) as well as the broadening of primary and memory CD8+ T cell responses (Halstead 2002, Bertram 2002). Signals moderated by CD137 have been shown to induce a novel subpopulation of CD11c+ CD8+ T cells that have strong anti-cancer and anti-autoimmune effects (Vinay 2006).  A novel carbohydrate-mediated interaction between CD137 and LGALS9 (Galectin-9 (Gal-9)) was identified and it was demonstrated in several immune responses that Gal-9 plays a significant role in CD137 signaling activities (Madireddi 2014). Gal-9 binds to terminal galactose moieties of N-linked glycans within the CRD4 region of CD137 and there is no competition between this binding with the binding of CD137 to its natural ligand CD137L or to agonist antibodies against CD137 (Bitra 2017). Bitra et al. also demonstrated that Gal-9 facilitates signaling and functional activation of CD137 in mouse T cells, DCs and NK cells upon binding mouse CD137L or agonist antibodies to CD137 (Bitra 2017). Once ligated and crosslinked, CD137 interacts with the tumor necrosis factor (TNF)-associated factors 1 and 2 ( TRAF1 and TRAF2), a process that leads to activation of the master immuno-regulatory transcription factor NF-κB (Chester 2016). In T cells, CD137 signaling results into upregulation of the anti-apoptotic B-cell lymphoma-extra large ( BCL2L1 (Bcl-xl)), B-cell lymphoma 2 ( BCL2) pathways and induces proliferation and production of pro-inflammatory cytokines interferon gamma ( IFNG (IFN-γ)) and IL2 (Lee 2002, Snell 2011). Additionally, CD137 stimulation causes an increase in signaling through the T-cell receptor (TCR) and amplifies the cytotoxicity of CD8+ T cells (Shuford 1997). Similarly, in NK cells, CD137 stimulation enhances proliferation, IFN-γ production, and cytolytic action (Melero 1998). In DCs, CD137 ligation speeds up maturation through upregulation of B7 co-stimulatory molecules ( CD80 and CD86) and elevates survival and production of IL6 and IL12 (Kuang 2012). Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models (Anderson 2012). The mode of action underlying CD137-mediated tumor regression consists of multiple, complimentary antitumor immune pathways. Mainly, CD137 agonism activates a potent, cytotoxic T-cell population that can infiltrate and lyse tumors (Curran 2013). In addition to direct tumor lysis, CD137 stimulation stimulates secretion of type 1 cytokines, creating an inflammatory, immunogenic cytokine milieu within the tumor microenvironment (Li 2003). Finally, CD137 ligation increases the secretion of perforin ( PRF1), granzyme and activation of the Fas ligand ( FASLG) effector system by both CD8+ T cells and NK cells (Morales-Kastresana 2013).

Implicated in

  
Entity Asthma
Note Polte et al. used a murine asthma model to demonstrate how a single injection of an anti-CD137 (CD137) mAb prevents the development of airway hyper reactivity, eosinophilic airway inflammation, excessive mucus production, and elevated IgE during a 7 week observation period. They further established that the disease is completely reversed by anti-CD137 mAb administration (Polte 2006).
  
  
Entity Human atherosclerosis
Note CD137 is expressed in human atherosclerosis and its activation promotes inflammation and disease development in murine atherosclerosis (Söderström 2014). Söderström et al. showed that the minor T allele of rs2453021 is associated with increased intima-media thickness in the common carotid artery and increased risk of incident non-cardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis (Söderström 2014).
  
  
Entity Crystalline silica-induced lung inflammation and fibrosis
Note Li et al. found that CD137 is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis. The CD137 pathway signaling was discovered to enhance inflammatory response and promote pulmonary fibrosis induced by crystalline silica (Li 2016).
  
  
Entity Colorectal cancer
Note Dimberg et al. investigated whether CD137 and CD137L protein levels are altered in colorectal tumours compared with paired normal tissues. They examined CD137 and CD137L plasma levels from patients with colorectal cancer . Collectively, they observed a significant lower CD137L level in cancerous tissue compared with paired normal tissue and the difference in CD137L protein level was significantly lower in the colon cancer subgroup compared with paired normal colon tissue. In addition, an elevated CD137 protein level in the rectal cancer subgroup compared with paired normal rectal tissue was observed. Higher soluble CD137 protein concentration was detected in the plasma of patients with a tumour localised in the colon compared to those with a tumour localised in the rectum. A tendency of higher CD137L protein concentration in the plasma from patients with colon tumour localization was observed. They also observed a strong correlation between plasma concentrations of CD137 and CD137L proteins. Their work revealed how different expression levels of CD137 and CD137L in the colon and rectum may indicate that various mechanisms are involved in the pathogenesis of colorectal cancer and lead to dissimilar protective immunity (Dimberg 2006).
  
  
Entity Crohn's disease
Note Maerten et al. investigated whether CD137/CD137L interactions might be involved in the pathogenesis of Crohn's disease (CD) and found that CD137 expression on lamina propria LP cells in inflamed and to a lesser extend in non-inflamed gut tissue from CD patients. They also found elevated CD137 mRNA levels in intestinal CD tissue. Their results suggest that CD137/CD137L interactions contribute to the persistence of gut inflammation in CD (Maerten 2004).
  
  
Entity Type 1 diabetes
Note Forsberg et al. reported suppression of type 1 diabetes (T1D) progression in NOD mice by CD137 deficiency. From their findings, blockage of the CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice and absence of CD137 or its interaction with CD137 ligand led to suppression of T1D progression. They also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. Their results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed (Forsberg 2017).
  
  
Entity Hodgkin lymphoma
Note Anderson et al. showed that CD137 protein is expressed by a selected group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms (Anderson 2012).
  
  
Entity Malignant and benign tumors
Note In the 32 healthy tissue samples they examined, none contained CD137-positive vessels while malignant tumors had a significantly enhanced frequency of CD137-expressing blood vessels (11/34). In benign tumors (2/14) and in inflammatory tissues (2/9) only a minority had CD137-expressing vessels (Broll 2001). Salih et al. described CD137 expression on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors (Salih 2000).
  

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Citation

This paper should be referenced as such :
Gjörloff Wingren A, Nyesiga B
TNFRSF9 (TNF receptor superfamily member 9);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/TNFRSF9ID42631ch1p36.html


External links

Nomenclature
HGNC (Hugo)TNFRSF9   11924
Cards
AtlasTNFRSF9ID42631ch1p36
Entrez_Gene (NCBI)TNFRSF9  3604  TNF receptor superfamily member 9
Aliases4-1BB; CD137; CDw137; ILA
GeneCards (Weizmann)TNFRSF9
Ensembl hg19 (Hinxton)ENSG00000049249 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000049249 [Gene_View]  ENSG00000049249 [Sequence]  chr1:7915871-7943165 [Contig_View]  TNFRSF9 [Vega]
ICGC DataPortalENSG00000049249
TCGA cBioPortalTNFRSF9
AceView (NCBI)TNFRSF9
Genatlas (Paris)TNFRSF9
WikiGenes3604
SOURCE (Princeton)TNFRSF9
Genetics Home Reference (NIH)TNFRSF9
Genomic and cartography
GoldenPath hg38 (UCSC)TNFRSF9  -     chr1:7915871-7943165 -  1p36.23   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)TNFRSF9  -     1p36.23   [Description]    (hg19-Feb_2009)
GoldenPathTNFRSF9 - 1p36.23 [CytoView hg19]  TNFRSF9 - 1p36.23 [CytoView hg38]
ImmunoBaseENSG00000049249
Mapping of homologs : NCBITNFRSF9 [Mapview hg19]  TNFRSF9 [Mapview hg38]
OMIM602250   
Gene and transcription
Genbank (Entrez)AK125490 AW449076 BC006196 BP381234 L12964
RefSeq transcript (Entrez)NM_001561
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)TNFRSF9
Cluster EST : UnigeneHs.738942 [ NCBI ]
CGAP (NCI)Hs.738942
Alternative Splicing GalleryENSG00000049249
Gene ExpressionTNFRSF9 [ NCBI-GEO ]   TNFRSF9 [ EBI - ARRAY_EXPRESS ]   TNFRSF9 [ SEEK ]   TNFRSF9 [ MEM ]
Gene Expression Viewer (FireBrowse)TNFRSF9 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3604
GTEX Portal (Tissue expression)TNFRSF9
Human Protein AtlasENSG00000049249-TNFRSF9 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ07011   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ07011  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ07011
Splice isoforms : SwissVarQ07011
PhosPhoSitePlusQ07011
Domaine pattern : Prosite (Expaxy)TNFR_NGFR_1 (PS00652)    TNFR_NGFR_2 (PS50050)   
Domains : Interpro (EBI)Growth_fac_rcpt_cys_sf    TNFR/NGFR_Cys_rich_reg    TNFR_9    TNFRSF9_N   
Domain families : Pfam (Sanger)TNFR_c6 (PF00020)   
Domain families : Pfam (NCBI)pfam00020   
Domain families : Smart (EMBL)TNFR (SM00208)  
Conserved Domain (NCBI)TNFRSF9
DMDM Disease mutations3604
Blocks (Seattle)TNFRSF9
SuperfamilyQ07011
Human Protein Atlas [tissue]ENSG00000049249-TNFRSF9 [tissue]
Peptide AtlasQ07011
HPRD03767
IPIIPI00549343   
Protein Interaction databases
DIP (DOE-UCLA)Q07011
IntAct (EBI)Q07011
FunCoupENSG00000049249
BioGRIDTNFRSF9
STRING (EMBL)TNFRSF9
ZODIACTNFRSF9
Ontologies - Pathways
QuickGOQ07011
Ontology : AmiGOplasma membrane  integral component of plasma membrane  apoptotic process  negative regulation of cell proliferation  external side of plasma membrane  tumor necrosis factor-mediated signaling pathway  signaling receptor activity  
Ontology : EGO-EBIplasma membrane  integral component of plasma membrane  apoptotic process  negative regulation of cell proliferation  external side of plasma membrane  tumor necrosis factor-mediated signaling pathway  signaling receptor activity  
Pathways : KEGGCytokine-cytokine receptor interaction   
REACTOMEQ07011 [protein]
REACTOME PathwaysR-HSA-5669034 [pathway]   
NDEx NetworkTNFRSF9
Atlas of Cancer Signalling NetworkTNFRSF9
Wikipedia pathwaysTNFRSF9
Orthology - Evolution
OrthoDB3604
GeneTree (enSembl)ENSG00000049249
Phylogenetic Trees/Animal Genes : TreeFamTNFRSF9
HOGENOMQ07011
Homologs : HomoloGeneTNFRSF9
Homology/Alignments : Family Browser (UCSC)TNFRSF9
Gene fusions - Rearrangements
Fusion : Fusion_HubGNPTG--TNFRSF9    KLHL21--TNFRSF9    MED1--TNFRSF9   
Fusion : QuiverTNFRSF9
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTNFRSF9 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TNFRSF9
dbVarTNFRSF9
ClinVarTNFRSF9
1000_GenomesTNFRSF9 
Exome Variant ServerTNFRSF9
ExAC (Exome Aggregation Consortium)ENSG00000049249
GNOMAD BrowserENSG00000049249
Varsome BrowserTNFRSF9
Genetic variants : HAPMAP3604
Genomic Variants (DGV)TNFRSF9 [DGVbeta]
DECIPHERTNFRSF9 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTNFRSF9 
Mutations
ICGC Data PortalTNFRSF9 
TCGA Data PortalTNFRSF9 
Broad Tumor PortalTNFRSF9
OASIS PortalTNFRSF9 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTNFRSF9  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTNFRSF9
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch TNFRSF9
DgiDB (Drug Gene Interaction Database)TNFRSF9
DoCM (Curated mutations)TNFRSF9 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TNFRSF9 (select a term)
intoGenTNFRSF9
NCG5 (London)TNFRSF9
Cancer3DTNFRSF9(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602250   
Orphanet
DisGeNETTNFRSF9
MedgenTNFRSF9
Genetic Testing Registry TNFRSF9
NextProtQ07011 [Medical]
TSGene3604
GENETestsTNFRSF9
Target ValidationTNFRSF9
Huge Navigator TNFRSF9 [HugePedia]
snp3D : Map Gene to Disease3604
BioCentury BCIQTNFRSF9
ClinGenTNFRSF9
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3604
Chemical/Pharm GKB GenePA36617
Clinical trialTNFRSF9
Miscellaneous
canSAR (ICR)TNFRSF9 (select the gene name)
DataMed IndexTNFRSF9
Probes
Litterature
PubMed120 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTNFRSF9
EVEXTNFRSF9
GoPubMedTNFRSF9
iHOPTNFRSF9
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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