Bilevel control of B-cell activation by the inositol 5-phosphatase SHIP

The balanced interplay between positive and negative signals pathways emanating from surface receptors has emerged as a common paradigm for regulation of cell function and the immune response. Here, we will review the recent progress in analysis of signaling pathways initiated upon antigen receptor (BCR) aggregation, and co-aggregation with the inhibitory IgG receptor FcgammaRIIB. Particular attention is paid to the function of the inositol 5-phosphatase SHIP and its effector p62i(Dok), a RasGAP adapter protein. SHIP and Dok function in FcgammaRIIB-mediated inhibition as well as in feedback regulation of signals generated through the BCR. These inhibitory molecules may play critical roles in the prevention of immune system hyperactivity and resulting autoimmunity.