Ca-dependent Ras/Erk signaling mediates negative selection of autoreactive B cells.

Signaling via the Ras/Erk pathway has long been recognized to be critical in lymphocyte development and function, yet the mechanisms that control the distinct functional outputs of this pathway in different cellular contexts remain poorly understood. Our recent results have demonstrated unexpected involvement of Ras/Erk signaling in the sensitization of B cells to apoptosis in order to eliminate autoreactive cells. Increases in cytosolic Ca(2+) are necessary and sufficient to induce activation of this Ras/Erk pathway, and the biochemical events involved in its activation are different from the ones involved in diacylglycerol (DAG)-mediated Ras/Erk activation. Developmental regulation of upstream mediators of these distinct pathways contributes to their predominant activation at different stages of B cell development. These findings have revealed a mechanism by which antigen stimulation can activate distinct Ras/Erk pathways at different developmental stages to mediate appropriate functional outputs that control the selection, development and activation of B cells. Despite these recent findings, however, much remains to be learned about the molecular mechanisms that confer functional specificity to common Ras/Erk signaling modules.