HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moreno-García, M. E. Articles by Santos-Argumedo, L. Search for Related Content PubMed PubMed Citation Articles by Moreno-García, M. E. Articles by Santos-Argumedo, L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

CD38 Signaling Regulates B Lymphocyte Activation via a Phospholipase C (PLC)-2-Independent, Protein Kinase C, Phosphatidylcholine-PLC, and Phospholipase D-Dependent Signaling Cascade¹

Miguel E. Moreno-García^*,, Lucia N. López-Bojórques, Alejandro Zentella, Lisa A. Humphries, David J. Rawlings and Leopoldo Santos-Argumedo^2,

^* Departments of Cell Biology and Molecular Biomedicine, Centro de Investigación y Estudios Avanzados, Mexico D.F. Mexico; Department of Cell Biology, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico D.F., Mexico; and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195

The CD38 cell surface receptor is a potent activator for splenic, B lymphocytes. The molecular mechanisms regulating this response, however, remain incompletely characterized. Activation of the nonreceptor tyrosine kinase, Btk, is essential for CD38 downstream signaling function. The major Btk-dependent substrate in B cells, phospholipase C-2 (PLC-2), functions to generate the key secondary messengers, inositol-1,4,5 trisphosphate and diacylglycerol. Surprisingly, CD38 ligation results in no detectable increase in phosphoinositide metabolism and only a minimal increase in cytosolic calcium. We hypothesized that Btk functioned independently of PLC-2 in the CD38 signaling pathway. Accordingly, we demonstrate that CD38 cross-linking does not result in the functional phosphorylation of PLC-2 nor an increase in inositol-1,4,5 trisphosphate production. Furthermore, splenic B cells exhibit a normal CD38-mediated, proliferative response in the presence of the phosphoinositide-PLC inhibitor, U73122. Conversely, protein kinase C (PKC) -deficient mice, or PKC inhibitors, indicated the requirement for diacylglycerol-dependent PKC isoforms in this pathway. Loss of PKC activity blocked CD38-dependent, B cell proliferation, NF-B activation, and subsequent expression of cyclin-D2. These results suggested that an alternate diacylglycerol-producing phospholipase must participate in CD38 signaling. Consistent with this idea, CD38 increased the enzymatic activity of the phosphatidylcholine (PC)-metabolizing enzymes, PC-PLC and phospholipase D. The PC-PLC inhibitor, D609, completely blocked CD38-dependent B cell proliferation, IB- degradation, and cyclin-D2 expression. Analysis of Btk mutant B cells demonstrated a partial requirement for Btk in the activation of both enzymes. Taken together, these data demonstrate that CD38 initiates a novel signaling cascade leading to Btk-, PC-PLC-, and phospholipase D-dependent, PLC-2-independent, B lymphocyte activation.

This article has been cited by other articles:

				F. Spadaro, C. Ramoni, D. Mezzanzanica, S. Miotti, P. Alberti, S. Cecchetti, E. Iorio, V. Dolo, S. Canevari, and F. Podo Phosphatidylcholine-Specific Phospholipase C Activation in Epithelial Ovarian Cancer Cells Cancer Res., August 15, 2008; 68(16): 6541 - 6549. [Abstract] [Full Text] [PDF]

				F. Malavasi, S. Deaglio, A. Funaro, E. Ferrero, A. L. Horenstein, E. Ortolan, T. Vaisitti, and S. Aydin Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology Physiol Rev, July 1, 2008; 88(3): 841 - 886. [Abstract] [Full Text] [PDF]

				J. C. Rodriguez-Alba, M. E. Moreno-Garcia, C. Sandoval-Montes, V. H. Rosales-Garcia, and L. Santos-Argumedo CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen Blood, April 1, 2008; 111(7): 3644 - 3652. [Abstract] [Full Text] [PDF]

				B. N. Kahner, R. T. Dorsam, S. R. Mada, S. Kim, T. J. Stalker, L. F. Brass, J. L. Daniel, D. Kitamura, and S. P. Kunapuli Hematopoietic lineage cell specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation Blood, October 1, 2007; 110(7): 2449 - 2456. [Abstract] [Full Text] [PDF]

				S. Deaglio, T. Vaisitti, R. Billington, L. Bergui, P. Omede', A. A. Genazzani, and F. Malavasi CD38/CD19: a lipid raft-dependent signaling complex in human B cells Blood, June 15, 2007; 109(12): 5390 - 5398. [Abstract] [Full Text] [PDF]

				S. Deaglio, T. Vaisitti, S. Aydin, E. Ferrero, and F. Malavasi In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia Blood, August 15, 2006; 108(4): 1135 - 1144. [Abstract] [Full Text] [PDF]

				F. E. Lund, H. Muller-Steffner, H. Romero-Ramirez, M. E. Moreno-Garcia, S. Partida-Sanchez, M. Makris, N. J. Oppenheimer, L. Santos-Argumedo, and F. Schuber 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 Int. Immunol., July 1, 2006; 18(7): 1029 - 1042. [Abstract] [Full Text] [PDF]