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Ellen Puré, William Davis, Hsiu-Ling Li
Wistar Institute, Philadelphia, PA
and Ludwig Institute for Cancer Research, New York, NY

Syk and Lyn Differentially Regulate BCR Mediated Activation of Akt, p70S6 Kinase, p90Rsk and MAP Kinase

The tyrosine kinases Syk and Lyn are activated in B lymphocytes following antibody induced cross-linking of the B cell receptor for antigen (BCR). We recently defined multiple protein tyrosine kinase (PTK)-dependent signaling pathways that link the BCR to the activation of several serine/threonine kinases, mitogen-activated protein kinase (MAPK), and members of two distinct families of ribosomal S6 kinases, p90Rsk and p70S6 kinase (p70S6k). We demonstrated that these pathways can be distinguished based on different requirements for BCR-mediated activation of the upstream PTKs, Syk and Lyn (a src-family kinase).

S6 kinases play important roles in regulating apoptosis, transition through the cell cycle, cytoskeletal reorganization and gene transcription in a variety of cell types. We found that activation of p70S6k is required for BCR-induced DNA synthesis. Therefore, we investigated the BCR-induced signal transduction pathways that lead to the activation of p70S6k in B cells. The activation of S6 kinases in other cell types occurs through the activation of the protooncogene Akt via a PTK and phosphotidyl-inositol 3-kinase (PI3-K)-dependent pathway. Consistent with this, we found that BCR mediates the phosphorylation of Akt in a PI3-kinase dependent manner. We also defined the roles of Syk and Lyn in regulating the phosphorylation of Akt. However, we obtained evidence for a second BCR-induced PTK-dependent signaling pathway that leads to the activation of p79S6k through an Akt-independent pathway. Delineation of these pathways is important for our understanding of antigen receptor mediated regulation of B cell function.