| Abstrakt: |
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 (PI3) and phospholipase Cγ (PLCγ), 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 CD19 and B-cell linker protein. These enzymes functions by generating both membrane-anchored and soluble second messenger molecules which regulated the activity of downstream signal transduction proteins. Active PI3K produces phosphatidylinositol-3,4-bisphosphate (PI(3,4)P[sub2]) and phosphatidylinositol-3,4-trisphosphate (PI(3,4,5)P[sub3]) which can bind to signalling 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)P[sub2] and PI(3,4,5)P[sub3] and therefore function to put a "brake" on the PI3K pathway. Active PLCγ produces inositol-1,4,5-triphosphate, 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 PLCγ activation is partially dependent on the PI(3,4,5)P[sub3] production by activated PI3K. Since PI3K and PLCγ also share common... [ABSTRACT FROM AUTHOR] |
