Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap 1 GTPase

In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap1 in B-cell receptor (BCR) signaling. PI3K produces lipids that rec ruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner Akt phosphorylates s everal transcription factors as well as proteins that regulate apoptosis an d protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinas e whose substrates include the nuclear factor of activated T cells (NF-AT)c l and beta-catenin transcriptional activators. In addition to Akt, PI3K-der ived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI 3K to the plasma membrane where its substrates are located. This is mediate d by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine- containing sequences on membrane-associated docking proteins. The docking p roteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perh aps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containi ng inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dep endent signaling. In contrast to PI3K, little is known about the Rap1 GTPas e. We showed that the BCR activates Rap1 via phospholipase C-dependent prod uction of diacylglycerol. Since Rap1 is thought to regulate cell adhesion a nd cell polarity it may be involved in B-cell migration.