CD40 (protein)

CD40 molecule, TNF receptor superfamily member 5
250px Rendering based on PDB 1CDF.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1CDF, 1CZZ, 1D00, 1FLL, 1LB6, 3QD6
Identifiers
Symbols	CD40 ; Bp50; CDW40; TNFRSF5; p50
External IDs	OMIM: 109535 MGI: 88336 HomoloGene: 954 ChEMBL: 1250358 GeneCards: CD40 Gene
Gene ontology Molecular function • antigen binding • signal transducer activity • receptor activity • protein binding • enzyme binding • ubiquitin protein ligase binding Cellular component • extracellular space • cytoplasm • plasma membrane • integral component of plasma membrane • external side of plasma membrane • cell surface • CD40 receptor complex • intracellular membrane-bounded organelle • extracellular exosome Biological process • positive regulation of protein phosphorylation • immune response-regulating cell surface receptor signaling pathway • protein complex assembly • cellular calcium ion homeostasis • inflammatory response • platelet activation • positive regulation of B cell proliferation • positive regulation of interleukin-12 production • B cell proliferation • positive regulation of tyrosine phosphorylation of Stat1 protein • defense response to protozoan • positive regulation of I-kappaB kinase/NF-kappaB signaling • positive regulation of MAP kinase activity • protein kinase B signaling • positive regulation of GTPase activity • positive regulation of transcription from RNA polymerase II promoter • positive regulation of isotype switching to IgG isotypes • regulation of immune response • regulation of immunoglobulin secretion • positive regulation of NF-kappaB transcription factor activity • defense response to virus • cellular response to lipopolysaccharide • cellular response to mechanical stimulus • positive regulation of protein kinase C signaling • positive regulation of endothelial cell apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE CD40 35150 at tn.png
File:PBB GE CD40 205153 s at tn.png
File:PBB GE CD40 215346 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	958	21939
Ensembl	ENSG00000101017	ENSMUSG00000017652
UniProt	P25942	P27512
RefSeq (mRNA)	NM_001250	NM_011611
RefSeq (protein)	NP_001241	NP_035741
Location (UCSC)	Chr 20: 46.12 – 46.13 Mb	Chr 2: 165.06 – 165.07 Mb
PubMed search	[1]	[2]

Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on T_H cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Deficiency can cause Hyper-IgM syndrome type 3.

Function

The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1, TRAF2, TRAF6 and possibly TRAF5 interact with this receptor serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

Specific effects on cells

In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L (CD154) on the T cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe.

The B cell can present antigens to helper T cells. If an activated T cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing resting B cell activation. The T cell also produces IL-2, which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited.

The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis (10)

Interactions

CD40 (protein) has been shown to interact with TRAF2, TRAF3, TRAF6, TRAF5 and TTRAP.