CONVERGENCE OF CD19 AND B-CELL ANTIGEN RECEPTOR SIGNALS AT MEK1 IN THE ERK2 ACTIVATION CASCADE

CD19 plays a critical role in regulating a cell responses to ng, We ha ve 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 extracell ular signal-regulated protein kinase 2 (ERK2) activation, in Daudi hum an 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, con sists of the sequential activation of the mitogen-activated protein ki nase (MAPK) cascade that includes Ras, Raf, MAPK kinase 1 (MEK1), and ERK2, Ligation of CD19 alone had little effect on these. CD19-mIgM col igation did not increase activation of I las or Raf beyond that induce d by ligation of mIgM alone. In contrast, coligation resulted in syner gistic 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 s eparate pathway by which CD19 regulates B cell function. Thus, the CD1 9-dependent signal after CD19-mIgM coligation converges with that gene rated by mIgM at MEK1, The intermediate kinases in the MAPK cascade le ading to ERK2 integrate signals from lymphocyte coreceptors.