The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Immunol Cell Biol. 2012 Oct;90(9):903-11. doi: 10.1038/icb.2012.31. Epub 2012 Jul 10.
Phosphatidylinositol-3 kinase (PI3K) activity is essential for normal B-cell receptor (BCR)-mediated responses. To understand the mechanisms of PI3K regulation during B-cell activation, we performed a series of biochemical analysis on primary B cells, and found that activity of Src family tyrosine kinases (SFK) is crucial for the activation of PI3K following BCR ligation and this is regulated by the SFK Lyn. We show that the hyperresponsive phenotype of B cells lacking Lyn is predicated on significantly increased basal and inducible PI3K activity that correlates with the constitutive hypophosphorylation of PAG/Cbp (phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk-binding protein), a concomitant reduction in bound Csk in Lyn(-/-) B cells and elevated levels of active Fyn. Regulating SFK activity may thus be a central mechanism by which Lyn regulates PI3K activity in B cells. This study defines the molecular connection between the BCR and PI3K and reveals this to be a point of Lyn-mediated regulation.
磷脂酰肌醇-3 激酶（PI3K）的活性对于正常 B 细胞受体（BCR）介导的反应是必不可少的。为了了解 B 细胞激活过程中 PI3K 调节的机制，我们对原代 B 细胞进行了一系列生化分析，发现 Src 家族酪氨酸激酶（SFK）的活性对于 BCR 连接后 PI3K 的激活至关重要，而这是由 SFK Lyn 调节的。我们表明，缺乏 Lyn 的 B 细胞的高反应表型是基于显著增加的基础和诱导的 PI3K 活性，这与 PAG/Cbp（与糖脂富集微区相关的磷酸蛋白/Csk 结合蛋白）的组成性低磷酸化相关，Lyn(-/-)B 细胞中结合的 Csk 减少，以及活性 Fyn 水平升高。因此，调节 SFK 活性可能是 Lyn 调节 B 细胞中 PI3K 活性的核心机制。这项研究定义了 BCR 和 PI3K 之间的分子连接，并揭示了这是 Lyn 介导的调节的一个关键点。
