International Immunology Advance Access originally published online on May 23, 2006
International Immunology 2006 18(7):1029-1042; doi:10.1093/intimm/dxl037
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CD38 induces apoptosis of a murine pro-B leukemic cell line by a tyrosine kinase-dependent but ADP-ribosyl cyclase- and NAD glycohydrolase-independent mechanism
1 Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983, USA
2 Institut Gilbert Laustriat, Département de Chimie Bioorganique UMR 7175 CNRS/ULP, Strasbourg-Illkirch, France
3 Departmento de Biomedicina Molecular, CINVESTAV-IPN, Mexico D.F., CP 07360 Mexico
4 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA
Correspondence to: F. E. Lund; E-mail: flund{at}trudeauinstitute.org
Cross-linking of CD38 on hematopoietic cells induces activation, proliferation and differentiation of mature T and B cells and mediates apoptosis of myeloid and lymphoid progenitor cells. In addition to acting as a signaling receptor, CD38 is also an enzyme capable of producing several calcium-mobilizing metabolites, including cyclic adenosine diphosphate ribose (cADPR). It has been previously postulated that the calcium-mobilizing metabolites produced by CD38 may regulate its receptor-based activities. To test this hypothesis, we examined whether the enzyme activity of CD38 controls the apoptosis of an anti-CD38-stimulated leukemic B cell. We show that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B cell line, is not affected by blocking the calcium-mobilizing activity of cADPR or by inhibiting intracellular or extracellular calcium mobilization. In addition, we demonstrate that blocking CD38 enzyme activity with 2'-deoxy-2'-fluoro-nicotinamide arabinoside adenine dinucleotide has no effect on apoptosis and that Ba/F3 cells expressing catalytically inactive mutant forms of CD38 still undergo apoptosis upon CD38 cross-linking. Instead, we find that anti-CD38-induced apoptosis is dependent on tyrosine kinase and caspase activation, and that this process appears to be potentiated by the presence of membrane microdomains. Thus, the receptor-mediated functions of CD38 can be separated from its enzyme activity in a murine leukemic cell line, suggesting that CD38 plays multiple, but independent, biologic roles.
Keywords: apoptosis, B lymphocytes, cell-surface molecules, signal transduction
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