Convergence of CD19 and B cell antigen receptor signals at MEK1 in the ERK2 activation cascade.
CD19 plays a critical role in regulating B cell responses to Ag. We have studied the mechanism by which coligation of CD19 and the B cell Ag receptor, membrane Ig (mIg), augments signal transduction, including synergistic enhancement of release of intracellular Ca2+ and extracellular signal-regulated protein kinase 2 (ERK2) activation, in Daudi human B lymphoblastoid cells. The pathway leading to ERK2 activation was further dissected to determine how signals derived from CD19 and mIgM interact. The best-defined pathway, known to be activated by mIgM, consists of the sequential activation of the mitogen-activated protein kinase (MAPK) cascade that includes Ras, Raf, MAPK kinase 1 (MEK1), and ERK2. Ligation of CD19 alone had little effect on these. CD19-mIgM coligation did not increase activation of Ras or Raf beyond that induced by ligation of mIgM alone. In contrast, coligation resulted in synergistic activation of MEK1. Furthermore, synergistic activation of ERK2 occurred in the absence of changes in intracellular Ca2+, and was not blocked by inhibition of protein kinase C activity and represents a separate pathway by which CD19 regulates B cell function. Thus, the CD19-dependent signal after CD19-mIgM coligation converges with that generated by mIgM at MEK1. The intermediate kinases in the MAPK cascade leading to ERK2 integrate signals from lymphocyte coreceptors.
Li
X
X
Department of Medicine, University of Alabama, Birmingham 35294, USA.
Carter
R H
RH
D018941:Antigens, CD19 / Q000502:physiology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002461:Cell Line, Transformed; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism / Q000502:physiology; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D018631:ras Proteins / Q000378:metabolism
D018941:Antigens, CD19; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D002118:Calcium