The CD38/CD157 mammalian gene family: An evolutionary paradigm for other leukocyte surface enzymes

Human CD38 is the mammalian prototype of a family of phylogenetically conserved proteins which share structural similarities and enzymatic activities involved in the production of an intracellular second messenger with calcium mobilizing effects. Engagement of CD38 by agonistic monoclonal antibodies and the CD31 ligand initiates a cytoplasmic signaling cascade involving tyrosine phosphorylation of the proto-oncogene c-cbl and of the extracellular regulated kinase 1 of 2 complex. Further requirements for signal transduction include a privileged localization within the cholesterol-rich areas of the plasma membrane and physical association with specialized surface receptors. CD38-mediated signals are crucial in heterotypic cell adhesion and migration as well as in the activation of proliferation/survival programs by normal and neoplastic cells. Here we review the most recent literature on this complex topic and attempt to formulate a single model reconciling the enzymatic and receptorial activities of CD38.