Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase C gamma pathways

Signal transduction through the B-cell antigen receptor (BCR) determines th e fare of B lymphocytes during their development and during immune response s. A multitude of signal transduction events are known to be activated by l igation of the BCR; however, the critical parameters determining the biolog ical outcome of the signal transduction cascade are only just beginning to be understood. Two enzymes which acton plasma membrane phospholipids, phosp hatidylinositol 3-kinase (PI3K) and phospholipase C gamma (PLC gamma), have been implicated as critical mediators of B-cell activation and differentia tion signals. Activation of these ubiquitous enzymes is regulated by B-lymp hocyte-specific signal transduction proteins, such as CD19 and B-cell linke r protein. These enzymes function by generating both membrane-anchored and soluble second messenger molecules which regulate the activity of downstrea m signal tranduction proteins. Active PI3K produces phosphatidylinositol-3, 4-bisphosphate (PI(3,4)P-2) and phosphatidylinositol-3,4-trisphosphate (PI( 3,4,5)P-3) which can bind to signaling proteins such as Btk or Akt via thei r pleckstrin homology domains, resulting in their membrane recruitment and activation. The lipid phosphatases SHIP and PTEN negatively regulate produc tion of PI(3,4)PI and PL(3,4,5)P-3 and therefore function to put a "brake" on the PI3K pathway Active PLC, produces inositol-l,4,5-trisphosphate, whic h regulates Ca2+ mobilization, and diacylglycerol, which binds to a subset of protein kinase C enzymes leading to their membrane localization and acti vation. Recent. evidence has indicated that PLC gamma activation is partial ly dependent on the PI(3,4,5)P-3 production by activated PI3K. Since PI3K a nd PLC gamma also share common downstream targets such as the NF-AT and NF- kappa B transcription factors, it is becoming clear that these two pathways are interconnected at several levels. Studies of mice deficient in compone nts of the PI3K and PLC gamma pathways demonstrate thai these pathways play critical roles in both pre-BCR and BCR-dependent selection events during B -cell differentiation. Taken together, the present data clearly indicate th at. PI3K and PLC gamma play critical and indispensable roles in the signal transduction cascades leading to multiple biological responses downstream o f the BCR.