Marshall A J, Niiro H, Yun T J, Clark E A
Department of Microbiology, University of Washington, Seattle, USA.
Immunol Rev. 2000 Aug;176:30-46. doi: 10.1034/j.1600-065x.2000.00611.x.
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.
通过B细胞抗原受体（BCR）进行的信号转导决定了B淋巴细胞在其发育过程以及免疫反应中的命运。已知大量信号转导事件可由BCR的连接激活；然而，决定信号转导级联反应生物学结果的关键参数才刚刚开始被理解。两种作用于质膜磷脂的酶，磷脂酰肌醇3激酶（PI3K）和磷脂酶Cγ（PLCγ），被认为是B细胞激活和分化信号的关键介质。这些普遍存在的酶的激活受B淋巴细胞特异性信号转导蛋白调控，如CD19和B细胞连接蛋白。这些酶通过产生膜锚定和可溶性第二信使分子发挥作用，这些分子调节下游信号转导蛋白的活性。活性PI3K产生磷脂酰肌醇-3,4-二磷酸（PI(3,4)P2）和磷脂酰肌醇-3,4,5-三磷酸（PI(3,4,5)P3），它们可通过其普列克底物蛋白同源结构域与信号蛋白如Btk或Akt结合，导致它们在膜上募集并激活。脂质磷酸酶SHIP和PTEN对PI(3,4)P2和PI(3,4,5)P3的产生起负调节作用，因此起到对PI3K途径“刹车”的作用。活性PLCγ产生肌醇-1,4,5-三磷酸，其调节Ca2+动员，以及二酰基甘油，它与一部分蛋白激酶C酶结合，导致它们在膜上定位并激活。最近的证据表明，PLCγ的激活部分依赖于活化的PI3K产生的PI(3,4,5)P3。由于PI3K和PLCγ也共享共同的下游靶点，如NF-AT和NF-κB转录因子，很明显这两条途径在多个层面相互连接。对PI3K和PLCγ途径成分缺陷小鼠的研究表明，这些途径在B细胞分化过程中的前BCR和BCR依赖性选择事件中都起着关键作用。综上所述，目前的数据清楚地表明，PI3K和PLCγ在导致BCR下游多种生物学反应的信号转导级联反应中起着关键且不可或缺的作用。
