SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling
SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling
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DOI：
10.1074/jbc.274.46.32662
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发表时间：
1999-11-12
影响因子：
4.8
通讯作者：
Scharenberg, AM
中科院分区：
文献类型：
--
作者：
Beitz, LO;Fruman, DA;Scharenberg, AM
我们最近已经证明，D3-磷酸肌醇磷脂酰肌醇3，4，5-三磷酸（PtdIns-3，4，5-P-3）是通过其在促进TEC家族酪氨酸激酶如布鲁顿酪氨酸激酶的功能中的作用产生持续的钙信号的关键。尽管PtdIns-3，4，5-P-3可潜在地由几种类型的磷酸肌醇3-激酶（PI 3 Ks）中的任何一种合成，但B细胞受体（BCR）诱导的PtdIns-3，4，5-P-3产生被认为主要通过Ia类（p85/p110）PI 3 Ks的活化而发生。已经提出该过程由Src家族激酶林恩和FISH的p85亚基之间的相互作用和/或通过CBL和/或CD 19介导的p85膜募集介导。然而，钙信号传导和其他PI 3 K依赖性信号在林恩激酶缺陷型B淋巴细胞系中相对保留，表明存在PI 3 K活化的替代途径。由于SYK/ZAP 70激酶是许多BCR启动的信号传导事件的上游，因此我们使用显性阴性和遗传敲除方法直接分析了B细胞受体信号传导中PtdIns-3，4，5-P-3和PtdIns-3，4-P-2的SYM依赖性蓄积。两种方法都表明SYK是BCR诱导的PtdIns-3，4，5-P-3生产的重要部分的上游，并且是必需的。尽管CD 19似乎不参与这种SYM依赖性途径，但SYK底物CEL可能参与其中，因为显性负性SYK显著减弱CBL酪氨酸磷酸化并完全阻断CBL与p85 PI 3 K的BCR依赖性缔合。
We have recently demonstrated that the D3-phosphoinositide phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P-3) is critical for producing sustained calcium signals through its role in promoting the function of TEC family tyrosine kinases such as Bruton's tyrosine kinase. Although PtdIns-3,4,5-P-3 can potentially be synthesized by any of several types of phosphoinositide 3-kinases (PI3Ks), B cell receptor (BCR)-induced PtdIns-3,4,5-P-3 production is thought to occur primarily through the activation of the class Ia (p85/p110) PI3Ks. This process has been proposed to be mediated by an interaction between the Src family kinase LYN and the p85 subunit of FISH and/or through p85 membrane recruitment mediated by CBL and/or CD19. However, calcium signaling and other PI3K-dependent signals are relatively preserved in a LYN kinase-deficient B lymphocyte cell line, suggesting that an alternative pathway for PI3K, activation exists. As SYK/ZAP70 kinases are upstream from many BCR-initiated signaling events, we directly analyzed SYM-dependent accumulation of both PtdIns-3,4,5-P-3 and PtdIns-3,4-P-2 in B cell receptor signaling using both dominant negative and genetic knockout approaches. Both methods indicate that SYK is upstream of, and necessary for, a significant portion of BCR-induced PtdIns-3,4,5-P-3 production. Whereas CD19 does not appear 60 be involved in this SYM-dependent pathway, the SYK substrate CEL is likely involved as the dominant negative SYK markedly attenuates CBL tyrosine phosphorylation and completely blocks the BCR-dependent association of CBL with p85 PI3K.