Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway.

Signal transduction through the B-cell antigen receptor (BCR) determines the fate of B lymphocytes during their development and during immune responses. A multitude of signal transduction events are known to be activated by ligation of the BCR; however, the critical parameters determining the biological outcome of the signal transduction cascade are only just beginning to be understood. Two enzymes which act on plasma membrane phospholipids, phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma (PLCgamma), have been implicated as critical mediators of B-cell activation and differentiation signals. Activation of these ubiquitous enzymes is regulated by B-lymphocyte-specific signal transduction proteins, such as CD 19 and B-cell linker protein. These enzymes function by generating both membrane-anchored and soluble second messenger molecules which regulate the activity of downstream signal transduction proteins. Active PI3K produces phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) and phosphatidylinositol-3,4-trisphosphate (PI(3,4,5)P3) which can bind to signaling proteins such as Btk or Akt via their pleckstrin homology domains, resulting in their membrane recruitment and activation. The lipid phosphatases SHIP and PTEN negatively regulate production of PI(3,4)P2 and PI(3,4,S)P3 and therefore function to put a "brake" on the PI3K pathway. Active PLCgamma produces inositol-1,4,5-trisphosphate, which regulates Ca2+ mobilization, and diacylglycerol, which binds to a subset of protein kinase C enzymes leading to their membrane localization and activation. Recent evidence has indicated that PLCgamma activation is partially dependent on the PI(3,4,5)P3 production by activated PI3K. Since PI3K and PLCgamma also share common downstream targets such as the NF-AT and NF-kappaB transcription factors, it is becoming clear that these two pathways are interconnected at several levels. Studies of mice deficient in components of the PI3K and PLCgamma pathways demonstrate that 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 that PI3K and PLCgamma play critical and indispensable roles in the signal transduction cascades leading to multiple biological responses downstream of the BCR.