Membrane-associated signaling in human B-lymphoma lines.
In B-non-Hodgkin lymphomas, Lyn and Cbp/PAG constitute the core of an oncogenic signalosome that captures the Phosphatidylinositol-3-kinase, the Spleen tyrosine kinase and the Signal transducer and activator of transcription-3 to generate pro-survival and proliferative signals. Lymphoma lines corresponding to follicular, mantle-cell and Burkitt-derived lymphomas display type-specific signalosome organizations that differentially activate PI3K, Syk and STAT3. In the follicular lymphoma line, PI3K, Syk and STAT3 were optimally activated upon association with the Lyn-Cbp/PAG signalosome, while in the Burkitt lymphoma-derived line, the association with Cbp/PAG and activation of PI3K were interfered with by the latent membrane proteins encoded by the Epstein-Barr virus. In the Jeko-1 mantle-cell line, a weak association of Syk with the Lyn-Cbp/PAG signalosome resulted in poor activation of Syk, but in those cells, as in the follicular and Burkitt-derived lines, efficient apoptosis induction by the Syk inhibitor R406 indicated that Syk is nonetheless an important prosurvival element and therefore a valuable therapeutic target. In all configurations described herein is the Lyn-Cbp/PAG signalosome independent of external signals and provides efficient means of activation for its associated lipid and protein kinases. In follicular and Burkitt-derived lines, Syk appears to be activated following binding to Cbp/PAG and no longer requires B-cell receptor-associated activation motifs for activation. Assessment of the different modalities of Lyn-Cbp/PAG signalosome organization could help in selecting the appropriate combination of kinase inhibitors to eliminate a particular type of lymphoma cells.
Tauzin
Sebastien
S
Department of Pathology and Immunology, Centre médical universitaire, 1, rue Michel-Servet, 1211 Geneva 11, Switzerland.
Ding
Heidrun
H
Burdevet
Dimitri
D
Borisch
Bettina
B
Hoessli
Daniel C
DC
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000201:enzymology*; D002051:Burkitt Lymphoma / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008224:Lymphoma, Follicular / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases