CD137

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; OMA:TNFRSF9 - orthologs
Gene location (Human)
Chr.	Chromosome 1 (human)
End	7,943,165 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	151,030,559 bp
RNA expression pattern
	Top expressed in
	lymph node; ; blood; ; appendix; ; monocyte; ; gallbladder; ; thymus; ; thymus; ; pancreatic ductal cell; ; spleen; ; rectum;
	Top expressed in
	thymus; ; lymph node; ; islet of Langerhans; ; uterus; ; morula; ; blood; ; spleen; ; subcutaneous adipose tissue; ; body of femur; ; Region I of hippocampus proper;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	cytokine binding; tumor necrosis factor-activated receptor activity; signaling receptor activity;
Cellular component	integral component of membrane; integral component of plasma membrane; membrane; external side of plasma membrane; extracellular space; plasma membrane;
Biological process	multicellular organism development; regulation of apoptotic process; response to lipopolysaccharide; inflammatory response; immune response; protein homotrimerization; apoptotic process; negative regulation of cell population proliferation; tumor necrosis factor-mediated signaling pathway; regulation of cell population proliferation; apoptotic signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	3604
	21942
	ENSG00000049249
	ENSMUSG00000028965
	Q07011
	P20334
	NM_001561
	NM_001077508; NM_001077509; NM_011612
	NP_001552
	NP_001070976; NP_001070977; NP_035742
	Wikidata
View/Edit Human	View/Edit Mouse

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.

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^[update] 5 clinical trials are active.^[11]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000049249 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000028965 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^a ^b Pfizer cancer drug shows promise in combo with Merck's Keytruda. May 2016
^ Phase 1 Study of Utomilumab (PF-05082566) In Combination with Rituximab in Patients with CD20+ NHL (Study B1641001)
^ PF-05082566 trials

External links

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

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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000049249 – Ensembl, May 2017

[refGRCm38Ensembl-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.

[pmid9464265-7] 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.

[pmid9418902-8] 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.

[Pfizer2016-05-9] 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

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v t e Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1–50	CD1 a-c 1A 1B 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50
51–100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100
101–150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150
151–200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200
201–250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249
251–300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299
301–350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD327 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350