CD137

CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule.

TNFRSF9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1D0J
Identifiers
Aliases	TNFRSF9, 4-1BB, CD137, CDw137, ILA, tumor necrosis factor receptor superfamily member 9, TNF receptor superfamily member 9
External IDs	OMIM: 602250 MGI: 1101059 HomoloGene: 1199 GeneCards: TNFRSF9
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.23 Start 7,915,894 bp[1] End 7,943,165 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 E2|4 81.52 cM Start 150,914,562 bp[2] End 150,946,102 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • cytokine binding • tumor necrosis factor-activated receptor activity • signaling receptor activity • receptor activity Cellular component • integral component of membrane • integral component of plasma membrane • membrane • external side of plasma membrane • extracellular • cell membrane Biological process • multicellular organism development • regulation of apoptotic process • negative regulation of interleukin-12 secretion • response to lipopolysaccharide • negative regulation of interleukin-10 secretion • inflammatory response • immune response • protein homotrimerization • apoptotic process • negative regulation of cell proliferation • tumor necrosis factor-mediated signaling pathway • regulation of cell proliferation • apoptotic signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3604	21942
Ensembl	ENSG00000049249	ENSMUSG00000028965
UniProt	Q07011	P20334
RefSeq (mRNA)	NM_001561	NM_001077508 NM_001077509 NM_011612
RefSeq (protein)	NP_001552	NP_001070976 NP_001070977 NP_035742
Location (UCSC)	Chr 1: 7.92 – 7.94 Mb	Chr 4: 150.91 – 150.95 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Expression

CD137 is expressed by activated T cells of both the CD4+ and CD8+ lineages.[5] Although it is thought to function mainly in co-stimulating those cell types to support their activation by antigen presenting cells expressing its ligand (CD137L), CD137 is also expressed on dendritic cells, B cells, NK cells, neutrophils and macrophages.[6]

Specific effects on cells

The best characterized activity of CD137 is its costimulatory activity for activated T cells. Crosslinking of CD137 enhances T cell proliferation, IL-2 secretion, survival and cytolytic activity. Further, it can enhance immune activity to eliminate tumors in mice.

Interactions

CD137 has been shown to interact with TRAF2.[7][8]

As a drug target

Utomilumab

Utomilumab (PF-05082566) targets this receptor to stimulate a more intense immune system attack on cancers.[9] It is a fully human IgG2 monoclonal antibody.[10] It is in early clinical trials.[9] As of June 2016 5 clinical trials are active.[11]

See also

• 4-1BB ligand
• Urelumab

References

1. GRCh38: Ensembl release 89: ENSG00000049249 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028965 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wehler TC, Karg M, Distler E, Konur A, Nonn M, Meyer RG, et al. (November 2008). "Rapid identification and sorting of viable virus-reactive CD4(+) and CD8(+) T cells based on antigen-triggered CD137 expression". Journal of Immunological Methods. 339 (1): 23–37. doi:10.1016/j.jim.2008.07.017. PMID 18760281.
6. Vinay DS, Kwon BS (July 2011). "4-1BB signaling beyond T cells". Cellular & Molecular Immunology. 8 (4): 281–4. doi:10.1038/cmi.2010.82. PMC 4002439. PMID 21217771.
7. Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS (January 1998). "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochemical and Biophysical Research Communications. 242 (3): 613–20. doi:10.1006/bbrc.1997.8016. PMID 9464265.
8. Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Molecular and Cellular Biology. 18 (1): 558–65. doi:10.1128/MCB.18.1.558. PMC 121523. PMID 9418902.
9. Pfizer cancer drug shows promise in combo with Merck's Keytruda. May 2016
10. Phase 1 Study of Utomilumab (PF-05082566) In Combination with Rituximab in Patients with CD20+ NHL (Study B1641001)
11. PF-05082566 trials

External links

• Human TNFRSF9 genome location and TNFRSF9 gene details page in the UCSC Genome Browser.

Further reading

• Kwon BS, Weissman SM (March 1989). "cDNA sequences of two inducible T-cell genes". Proceedings of the National Academy of Sciences of the United States of America. 86 (6): 1963–7. Bibcode:1989PNAS...86.1963K. doi:10.1073/pnas.86.6.1963. PMC 286825. PMID 2784565.
• Schwarz H, Tuckwell J, Lotz M (December 1993). "A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family". Gene. 134 (2): 295–8. doi:10.1016/0378-1119(93)90110-O. PMID 8262389.
• Sica G, Chen L (2000). "Biochemical and immunological characteristics of 4-1BB (CD137) receptor and ligand and potential applications in cancer therapy". Archivum Immunologiae et Therapiae Experimentalis. 47 (5): 275–9. PMID 10604232.
• Schwarz H (March 2005). "Biological activities of reverse signal transduction through CD137 ligand". Journal of Leukocyte Biology. 77 (3): 281–6. doi:10.1189/jlb.0904558. PMID 15618293.
• Kwon BS, Weissman SM (March 1989). "cDNA sequences of two inducible T-cell genes". Proceedings of the National Academy of Sciences of the United States of America. 86 (6): 1963–7. Bibcode:1989PNAS...86.1963K. doi:10.1073/pnas.86.6.1963. PMC 286825. PMID 2784565.
• Zhou Z, Kim S, Hurtado J, Lee ZH, Kim KK, Pollok KE, Kwon BS (February 1995). "Characterization of human homologue of 4-1BB and its ligand". Immunology Letters. 45 (1–2): 67–73. doi:10.1016/0165-2478(94)00227-I. PMID 7622190.
• Alderson MR, Smith CA, Tough TW, Davis-Smith T, Armitage RJ, Falk B, et al. (September 1994). "Molecular and biological characterization of human 4-1BB and its ligand". European Journal of Immunology. 24 (9): 2219–27. doi:10.1002/eji.1830240943. PMID 8088337.
• Schwarz H, Tuckwell J, Lotz M (December 1993). "A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family". Gene. 134 (2): 295–8. doi:10.1016/0378-1119(93)90110-O. PMID 8262389.
• Schwarz H, Blanco FJ, von Kempis J, Valbracht J, Lotz M (April 1996). "ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival". Blood. 87 (7): 2839–45. doi:10.1182/blood.V87.7.2839.bloodjournal8772839. PMID 8639902.
• Loo DT, Chalupny NJ, Bajorath J, Shuford WW, Mittler RS, Aruffo A (March 1997). "Analysis of 4-1BBL and laminin binding to murine 4-1BB, a member of the tumor necrosis factor receptor superfamily, and comparison with human 4-1BB". The Journal of Biological Chemistry. 272 (10): 6448–56. doi:10.1074/jbc.272.10.6448. PMID 9045669.
• Schwarz H, Arden K, Lotz M (June 1997). "CD137, a member of the tumor necrosis factor receptor family, is located on chromosome 1p36, in a cluster of related genes, and colocalizes with several malignancies". Biochemical and Biophysical Research Communications. 235 (3): 699–703. doi:10.1006/bbrc.1997.6870. PMID 9207223.
• Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Molecular and Cellular Biology. 18 (1): 558–65. doi:10.1128/MCB.18.1.558. PMC 121523. PMID 9418902.
• Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS (January 1998). "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochemical and Biophysical Research Communications. 242 (3): 613–20. doi:10.1006/bbrc.1997.8016. PMID 9464265.
• Kim YJ, Kim SH, Mantel P, Kwon BS (March 1998). "Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses". European Journal of Immunology. 28 (3): 881–90. doi:10.1002/(SICI)1521-4141(199803)28:03<881::AID-IMMU881>3.0.CO;2-0. PMID 9541583.
• Saoulli K, Lee SY, Cannons JL, Yeh WC, Santana A, Goldstein MD, et al. (June 1998). "CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand". The Journal of Experimental Medicine. 187 (11): 1849–62. doi:10.1084/jem.187.11.1849. PMC 2212301. PMID 9607925.
• Langstein J, Michel J, Schwarz H (November 1999). "CD137 induces proliferation and endomitosis in monocytes". Blood. 94 (9): 3161–8. doi:10.1182/blood.V94.9.3161. PMID 10556203.
• Jang LK, Lee ZH, Kim HH, Hill JM, Kim JD, Kwon BS (December 2001). "A novel leucine-rich repeat protein (LRR-1): potential involvement in 4-1BB-mediated signal transduction". Molecules and Cells. 12 (3): 304–12. PMID 11804328.
• Cooper D, Bansal-Pakala P, Croft M (February 2002). "4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity". European Journal of Immunology. 32 (2): 521–9. doi:10.1002/1521-4141(200202)32:2<521::AID-IMMU521>3.0.CO;2-X. PMID 11828369.
• Wilcox RA, Chapoval AI, Gorski KS, Otsuji M, Shin T, Flies DB, et al. (May 2002). "Cutting edge: Expression of functional CD137 receptor by dendritic cells". Journal of Immunology. 168 (9): 4262–7. doi:10.4049/jimmunol.168.9.4262. PMID 11970964.
• Shulzhenko N, Morgun A, Chinellato AP, Rampim GF, Diniz RV, Almeida DR, Gerbase-DeLima M (March 2002). "CD27 but not CD70 and 4-1BB intragraft gene expression is a risk factor for acute cardiac allograft rejection in humans". Transplantation Proceedings. 34 (2): 474–5. doi:10.1016/S0041-1345(02)02600-3. PMID 12009595.
• Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H (July 2002). "CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers". Journal of Leukocyte Biology. 72 (1): 35–42. PMID 12101260.