CD137 TNFRSF9 (tumor necrosis factor receptor superfamily, member 9), ILA (induced by lymphocyte activation), 4-1BB, CDw137
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
T Cell
B Lymphocyte
Monocyte
Epithelial Cell
Hepatoma Cell
T Lymphocyte
Dendritic Cell, Follicular
Macrophage
Fibroblast
39 / 39
83 / 83

Expression
CD137 (was CDw137) expression is induced on T and B lymphocytes, and is especially high on CD45RA and CD45R0 transitional T cell subsets.  Transcripts encoding CD137 are also expressed on B lymphocytes, follicular dendritic cells, monocytes, epithelial and hepatoma cells.  A mRNA splice of the murine CD137 (4-1BB) was identified that encodes a soluble form of murine CD137. The full length and spliced isoforms of the CD137 mRNA are differentially expressed and regulated on murine T cells, macrophages, 3T3 fibroblasts and epitheloid cells.  CD137 mRNA is absent from resting T cells but on activation is induced on T and B cells and in monocytes.  It is also detected on activated non-lymphoid cells. Expression on the surface of activated human T cells has been demonstrated with peptide antibodies. Peptide antibodies showed that mouse CD137 is expressed on activated thymocytes and activated splenic T cells, CD4+ and CD8+ T cells.  Mouse CD137 mRNA was not found on activated B cells.



Structure
MOLECULAR FAMILY NAME: Belongs to the tumor necrosis factor receptor family.

CD137 is a single-pass type-1 255 aa glycoprotein.  It contains an 186 aa extracellular domain which contains 3 cysteine-rich motifs and 2 potential N-glycosylation sites, a 22 aa transmembrane domain and a short 47 aa N-terminal cytoplasmic domain containing potential phosphorlation sites.  CD137 was originally identified as the molecule induced by lymphocyte activation (ILA).  CD137 was cloned and found to be a member of the TNF-R family and is the human orthologue of murine 4-1BB.  The 2nd and 3rd Cys residues in the 1st repeat of CD137 are not adjacent, as they are in the 1st repeats of other members of this superfamily.  They are separated by 2 aa, as they are in a typical 2nd repeat.  The cytoplasmic domain of mouse CD137 contains a sequence, CSCRCP, which resembles the CXCP motif for the Lck recognition site found in CD4 and CD8.  Human CD137 has a slightly different sequence CSCRFP.  The cytoplasmic domain contains a high proportion of consecutive aa acidic residues. 

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
CEM (human T lymphoma) and T cells - 85 kDa 39 kDa

MOLECULAR MASS OF 4-1BB 
Cell Type Unreduced Reduced
97 kDa 50 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Differential splicing yields to the release of a 16 kDa soluble form from activated T cells.

POST-TRANSLATIONAL MODIFICATION

There are 2 potential N-linked glycosylation sites.

Ligands
CD137 is a receptor which binds to 4-1BBL, a co-stimmulatory molecule, and is a type-2 membrane protein of the TNF superfamily.  CD137 has been reported to bind to the extracellular matrix.  Lck is co-precipitated with mouse CD137 and Cys20 and Cys23 of Lck are critical for the association.

LIGANDS AND MOLECULES ASSOCIATED WITH CD137
Molecule Comment
4-1BB ligand A type-2 transmembrane protein which is a member of the TNF ligand family of molecules



Function
CD137 acts as a co-stimulator of T cell proliferation and contributes to the clonal expansion, survival and development of T cells.  T cell CD137 interacts with the CD137 ligand on antigen prfesenting cells, leading to costimulation and apoptosis.  It induces proliferation in peripheral monocytes, enhances T cell costimulation and apoptosis by TCR/CD3 triggered activation and regulates CD28 co-stimulation to promote Th1 cell responses.  B cell CD137 ligand interacts on follicular dendritic cells leading to B cell proliferation and increased Ig synthesis.  CD137 and their related ligands are important regulators of a wide variety of physiologic processes and play an important role in the regulation of immune responses.  CD137 protein induces activation of monocytes which  requires immobilization of the CD137 protein, indicating that activation via CD137 is mediated by crosslinking of a corresponding ligand/co-receptor expressed on monocytes.  TRAF adaptor proteins have been shown to bind to CD137 receptor and transduce the signals leading to activation of NF-κB.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD137 IN INTACT ANIMAL

CD137 is found in the sera of rheumatoid arthritis patients. A soluble form of CD137 (sCD137) is generated by differential splicing and seems to be expressed selectively by activated lymphocytes.  sCD137 is present at low levels in sera of some healthy donors and is significantly enhanced in sera of patients with rheumatoid arthritis.  CD137 eradicates established tumors.  Anti-4-1BB mAb has been shown to eradicate established large tumors in mice.  Susceptible tumors include the poorly immunogenic Ag104A sarcoma and the highly tumorigenic P815 mastocytoma.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD137: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD137: No information.

ADDITIONAL INSIGHTS

In humans the gene for CD137 is located in chromosomal region that contains the genes for several other members of the TNF-R family.  It is associated with deletions and rearrangements in several malignancies.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3604Q07011
MouseB32393P20334J04492
MouseP41274L15435
Antibodies
4B4   View Reactivity
4B4-1   View Reactivity

Revised June 25, 2008


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