Regulation of the PI 3-kinase pathway and the Ras pathway in B cell receptor signaling

The B cell receptor (BCR) initiates several signaling pathways that combine to induce different responses such as cell death, anergy, proliferation and differentiation. BCR signaling occupies a major role in the development of the immune system and in the immune response to pathogens. Two major signaling pathways activated by the BCR are the Ras pathway and the PI 3-kinase pathway. The GTP-binding protein Ras induces the activation of the kinase ERK, which has a number of cytoplasmic and nuclear targets. PI 3-kinase generates 3-phosphoinositides which allow the membrane translocation and activation of cytosolic kinases such as the serine/threonine kinase Akt. There is evidence from various systems that the PI 3-kinase and the Ras pathways cross-regulate each other. As this issue is crucial to the understanding of BCR signaling we have examined it in marine splenic B cells.; Our findings indicate that the Ras target ERK is also dependent on PI 3-kinase, the activity of Phospholipase C-γ2 and on intracellular calcium mobilization. Furthermore, the activation of PI 3-kinase itself is dependent on Ras. This indicates that these two major signaling pathways are intricately connected and form part of a signaling network in B cells.; The BCR response is blocked by the co-clustering of the IgG receptor FcγRIIb. This ‘negative signaling’ is thought to regulate both the immune response and the maintenance of self-tolerance. The PI 3-kinase pathway in other systems controls proliferation and cell survival through the kinase Akt. Because these responses are blocked by negative signaling, we examined Akt activation in B cells. We have found that Akt is activated by the BCR but downregulated under negative signaling. This is not because of a lack of PI 3-kinase activation, but because of the consumption of its product by the inositol 5-phosphatase SHIP, previously shown to be a mediator of negative signaling. Thus we have extended the role of SHIP in B cells to include the negative regulation of the PI 3-kinase pathway.; In summary this work demonstrates multilayered control of the effector kinases Erk and Akt by the BCR and its coreceptor FcγRIIb.