Structural and functional characteristics of the human CD38 molecule. In human B cells, CD38 is expressed as an integral surface membrane molecule, often in a dimeric conformation. As an enzyme, CD38 may interact with the substrate ligands NAD⁺ and NADP⁺, which are converted to cADPR, ADPR, and NAADP, all intracellular Ca²⁺-mobilizing agents. CD38 also interacts with non-substrate ligands, including CD31 and hyaluronic acid, which regulate cell-cell and cell-matrix contacts. On the plasma membrane, CD38 displays preferential localization in membrane lipid microdomains in close contact with the BCR complex (CD19/CD81) and with molecules regulating homing (CXCR4 and CD49d). CD38 engagement by means of the natural ligand CD31 (or surrogate agonistic mAb) triggers the activation of an intracellular signaling pathway, which includes ZAP-70 and ERK1/2 as major players. These signals increase chemotaxis as well as proliferation of neoplastic B cells. The interplay between the enzymatic and receptor activities still needs to be determined in the CLL context.