title: A novel Lyn-protein kinase Cδ/ε-protein kinase D axis is activated in B cells by signalosome-independent alternate pathway BCR signaling.
abstract: BCR signaling initiates multiple activities critical for B-cell function. Recently, we identified an alternate BCR signaling pathway, induced by IL-4, that is signalosome-independent, unlike the classical signalosome-dependent pathway, and that leads to activation of the MAP kinase, ERK. Here we questioned whether alternate pathway signaling extends to other key downstream events, especially protein kinase D (PKD) activation. We found that in murine spleen-derived B cells the IL-4-induced alternate pathway for BCR signaling results in PKD and PKD substrate phosphorylation, and that alternate pathway phosphorylation of HDAC5/7 and other key substrates requires PKD. Furthermore, we found that tyrosine phosphorylation of PKCδ/ε occurs as a result of alternate but not classical pathway signaling and is required for phosphorylation of PKD and PKD substrates. This result identifies PKCδ/ε tyrosine phosphorylation as a unique outcome of the alternate pathway. The alternate pathway is mediated by Lyn that is not required for classical pathway signaling and we found that Lyn associates directly with PKCδ/ε and is required for phosphorylation of PKCδ/ε and of PKD. These findings indicate that IL-4 influences B-cell activation by inducing a novel signaling pathway from BCR to Lyn to PKCδ/ε to PKD.
authors: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. bguo@nshs.edu
authors: Benchang
authors: B
authors: Guo
authors: Thomas L
authors: TL
authors: Rothstein
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013154:Spleen / Q000166:cytology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D011947:Receptors, Antigen, B-Cell; D015847:Interleukin-4; C089212:protein kinase D; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon