Ligation of the B cell antigen receptor (BCR) induces a cascade of signaling pathways that lead to clonal expansion, differentiation, or abortive activation-induced apoptosis of B lymphocytes. BCR-mediated cross-linking induces the rapid phosphorylation of protein tyrosine kinases. However, the pathways leading to the activation of downstream serine/threonine kinases such as mitogen-activated protein kinase, p90Rsk , and p70S6 kinase (p70 S6k ) that mediate reorganization of the actin cytoskeleton, cell cycle progression, gene transcription, and protein synthesis have not been delineated. We recently demonstrated that cross-linking of BCR leads to activation of p70 S6k in B lymphocytes. In this report, we demonstrate that multiple protein tyrosine kinase-dependent signal transduction pathways induced by BCR lead to the activation of p70 S6k . These distinct pathways exhibit different thresholds with respect to the extent of receptor cross-linking required for their activation. Activation of p70S6k by suboptimal doses of anti-Ig is Sykdependent and is mediated by protein kinase C and phosphoinositol 3-kinase. Moreover, the activation of p70S6k results in phosphorylation of S6 protein which is important for ribosomal protein synthesis and may be coupled to BCR-induced protein and DNA synthesis in primary murine B cells.
Ligation of the antigen receptor (BCR)1 can lead to clonal expansion, differentiation, or abortive activation-induced apoptosis of B lymphocytes. Several early signaling events induced by ligation of BCR have been described including the rapid activation of protein tyrosine kinases, calcium mobilization, and activation of downstream serine/threonine kinases (1-8). These early events are followed by cytoskeletal reorganization, induced gene expression, and increased mRNA and protein synthesis (9). The relationship between the defined early signal transduction events, intermediate signaling events, and the fate of B cells is not clear.We have been investigating the protein tyrosine kinase-dependent regulation of BCR-mediated activation of serine/threonine kinases. We demonstrated that ligation of BCR on the avian B cell line DT40 results in activation of mitogen-activated protein kinase (MAPK) and members of two families of ribosomal S6 kinases, p90Rsk and p70S6 kinase (p70 S6k ) (10). Ribosomal S6 kinases are highly conserved proteins that are critical for translational regulation particularly of genes containing poly-pyrimidine tracts in their 5Ј-untranslated regions that encode essential components of the protein synthesis apparatus (11-15). These kinases can regulate mRNA translation through phosphorylation of ribosomal S6 protein. Although both p90Rsk and p70 S6k can phosphorylate S6 in vitro, p70S6k