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The Journal of Immunology, 1999, 162: 2693-2702.
Copyright © 1999 by The American Association of Immunologists

CD38 Signaling in B Lymphocytes Is Controlled by Its Ectodomain but Occurs Independently of Enzymatically Generated ADP-Ribose or Cyclic ADP-Ribose1

Frances E. Lund2,*, Hélène M. Muller-Steffner{dagger}, Naixuan Yu*, C. David Stout{ddagger}, Francis Schuber{dagger} and Maureen C. Howard3,*

* DNAX Research Institute, Palo Alto, CA 94304; {dagger} Laboratoire de Chimie Bioorganique, Unité Mixte de Recherche 7514 Centre National de la Recherche Scientifique-Université Louis Pasteur, Faculté de Pharmacie, Illkirch, France; and {ddagger} Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037

CD38 is a type II transmembrane glycoprotein that is expressed by many cell types including lymphocytes. Signaling through CD38 on B lymphocytes can mediate B cell activation, proliferation, and cytokine secretion. Additionally, coligation of CD38 and the B cell Ag receptor can greatly augment B cell Ag receptor responses. Interestingly, the extracellular domain of CD38 catalyzes the conversion of NAD+ into nicotinamide, ADP-ribose (ADPR), and cyclic ADPR (cADPR). cADPR can induce intracellular calcium release in an inositol trisphosphate-independent manner and has been hypothesized to regulate CD38-mediated signaling. We demonstrate that replacement of the cytoplasmic tail and the transmembrane domains of CD38 did not impair CD38 signaling, coreceptor activity, or enzyme activity. In contrast, independent point mutations in the extracellular domain of CD38 dramatically impaired signal transduction. However, no correlation could be found between CD38-mediated signaling and the capacity of CD38 to catalyze an enzyme reaction and produce cADPR, ADPR, and/or nicotinamide. Instead, we propose that CD38 signaling and coreceptor activity in vitro are regulated by conformational changes induced in the extracellular domain upon ligand/substrate binding, rather than on actual turnover or generation of products.




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