CD40 molecule, TNF receptor superfamily member 5
Rendering based on PDB 1CDF.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 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 • signal transducer activity • receptor activity • protein binding • enzyme binding Cellular component • extracellular region • plasma membrane • plasma membrane • integral to plasma membrane • external side of plasma membrane • CD40 receptor complex • intracellular membrane-bounded organelle Biological process • positive regulation of protein phosphorylation • immune response-regulating cell surface receptor signaling pathway • protein complex assembly • cellular calcium ion homeostasis • inflammatory response • signal transduction • platelet activation • positive regulation of B cell proliferation • positive regulation of interleukin-12 production • positive regulation of Rac GTPase activity • B cell proliferation • positive regulation of tyrosine phosphorylation of Stat1 protein • positive regulation of Cdc42 GTPase activity • positive regulation of I-kappaB kinase/NF-kappaB cascade • positive regulation of MAP kinase 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 mechanical stimulus • positive regulation of protein kinase C signaling cascade • positive regulation of endothelial cell apoptosis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	958	21939
Ensembl	ENSG00000101017	ENSMUSG00000017652
UniProt	P25942	P27512
RefSeq (mRNA)	NM_001250.4	NM_011611.2
RefSeq (protein)	NP_001241.1	NP_035741.2
Location (UCSC)	Chr 20: 44.75 – 44.76 Mb	Chr 2: 164.88 – 164.9 Mb
PubMed search	[1]	[2]
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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 [link]

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 and 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.^[1]

Specific effects on cells [link]

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-4, 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 switchingor 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 [link]

CD40 (protein) has been shown to interact with TRAF2,^[2][3][4] TRAF3,^[3][5][6][7] TRAF6,^[3][7] TRAF5^[3][8] and TTRAP.^[9]

References [link]

• Carlring, Jennifer; AlTaher HM, Clark S, Chen X, Latimer SL, Jenner T, Buckle AM, Heath AW (2011). "CD154-CD40 interactions in the control of B cell hematopoiesis". J.Leuk Biol 89 (5): 697–706. DOI:10.1189/jlb.0310179. 

Further reading [link]