Friday, October 14, 2011

Biology of CD38

Although originally defined as a T-cell activation molecule, CD38 expression is found on other cell lineages. Within the B-cell compartment, CD38 is expressed by B lineage blasts in bone marrow and by B lymphocytes in germinal centers, activated tonsils, and by plasma cells. Mature virgin and memory B cells express only low levels of the molecule. CD38 also has been found in pancreatic acinar cells, smooth muscle cells, osteoclasts, and in different areas of the brain, although in most of these instances, CD38 is found in the cytosol and/or in the nucleus and not on the cell membrane.

The protein encoded by CD38 is a single chain type II transmembrane molecule displaying a molecular weight of ∼ 45 kDa. The functional CD38 molecule is a dimer, with the central part between the two monomers hosting the catalytic site. The monomer to dimer transition controls the functions of the molecule. Additional control is made by how the CD38 is arranged in lipid microdomains of the plasma membrane where the molecule has a tendency to associate with other proteins, forming large supramolecular complexes. CD38-associated molecules in human B cells include the CD19/CD81 complex, the chemokine receptor CXCR4, and adhesion molecules such as CD49d. CD38 is also found in exosomes, membrane vesicles secreted by B cells, and is probably part of an intercellular communication network.

An initial function attributed to CD38 was the regulation of activation/ proliferation of human T lymphocytes. Stimulating monoclonal antibodies (mAbs) specific for CD38 induce rapid Ca2+ fluxes and trigger the phosphorylation of a cascade of intracellular substrates, leading to activation of the NF-κB complex. Protracted effects include initiation of genetic programs causing cytokine secretion and proliferation of T lymphocytes. CD31 (also known as PECAM-1) is a non-substrate CD38 ligand that can start the signaling cascade and recapitulate the biologic events observed in vitro using surrogate agonistic mAbs.

The functional properties of CD38 on human B cells appear to be strictly linked to the stage of maturation. Blocking mAbs in cultures of CD19+ B-cell precursors on stromal layers markedly suppresses B-cell lymphopoiesis by inducing apoptosis. Opposite effects are observed in mature circulating B lymphocytes and tonsillar germinal center B cells, where CD38 ligation is followed by activation, apoptosis inhibition, proliferation, and cytokine secretion. In both instances, the mechanisms are attributed to the activation of an intracellular signaling pathway ruled by CD38 and requiring an association with CD19. The ensuing phosphorylation cascade includes lyn and phosphatidylinositol 3-kinase, among other kinases.

CD38 has a striking similarity to the enzyme adenosine diphosphate (ADP) ribosyl cyclase. This enzyme has the unique characteristic of cyclizing NAD+ to generate cyclic ADP ribose (cADPR), a second messenger that releases Ca2+ from internal stores, independently of the IP3 pathway. cADPR is a ubiquitous second messenger in eukaryotic cells. A further enzymatic activity recently attributed to CD38 is the pH-dependent conversion of NADP+ to NAADP+. These products bind different receptors and channels involved in the regulation of Ca2+ and activating critical signaling pathways.

How these varied functional activities can be conducted by a single molecule is yet to be defined.

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