apoptosis ͉ inositol phosphate ͉ lymphocyte ͉ Rasa3 C ross-linking of the antigen receptor on T and B lymphocytes by antigen is followed by the rapid activation of phospholipase C␥, resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the production of inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol. Ins(1,4,5)P 3 causes release of calcium from the endoplasmic reticulum and is the substrate of two main metabolic pathways. Dephosphorylation by type I Ins(1,4,5)P 3 5-phosphatase generates the inactive metabolite inositol 1,4-bisphosphate (1, 2). Phosphorylation by isoforms A, B, and C of Ins(1,4,5)P 3 3-kinase (Itpkb) or inositol polyphosphate multikinase results in the production of inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P 4 ] (3). In various cellular systems, it has been demonstrated that Ins(1,3,4,5)P 4 is a modulator of Ins(1,4,5)P 3 levels and calcium mobilization (3-5). However, Ins(1,4,5)P 3 and calcium concentrations in response to T cell antigen receptor stimulation were found normal in double-positive thymocytes from Itpkb-deficient mice, despite an important decrease in Ins(1,3,4,5)P 4 production resulting in profound defects in the final maturation of these cells (6, 7). Alternative pathways to mediate the cellular effects of Ins(1,3,4,5)P 4 include the binding to pleckstrin homology (PH) domains of specific proteins acting as Ins(1,3,4,5)P 4 receptor, and the synthesis of higher inositol phosphates (8).To assess the potential contribution of the Ins(1,4,5)P 3 -ItpkbIns(1,3,4,5)P 4 signaling pathway to B cell function and development, we have analyzed the B cell lineage of Itpkb Ϫ/Ϫ mice. Our results indicate that Itpkb and Ins(1,3,4,5)P 4 mediate a survival signal in B cells by regulating Erk signaling pathway and proapoptotic Bim gene expression.
