TAPP1 and TAPP2 are targets of phosphatidylinositol 3-kinase signaling in B cells: Sustained plasma membrane recruitment triggered by the B-cell antigen receptor
TAPP1 and TAPP2 are targets of phosphatidylinositol 3-kinase signaling in B cells: Sustained plasma membrane recruitment triggered by the B-cell antigen receptor
复制标题
DOI：
10.1128/mcb.22.15.5479-5491.2002
复制
发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Hou, S
中科院分区：
文献类型：
--
作者：
Marshall, AJ;Krahn, AK;Hou, S
我们报道了两种与Bam32相关的信号转导蛋白的特性，它们被称为TAPP1和TAPP2。Bam32、TAPP1和TAPP2具有一些共同特征，包括分子量小（32到47 kDa）、无酶结构域、在人类和小鼠之间高度保守，以及在其C末端附近存在包含3 - 磷酸肌醇结合基序的普列克底物蛋白同源（PH）结构域。与Bam32不同的是，TAPP1和TAPP2的N末端区域包含第二个PH结构域。TAPP1和TAPP2的转录本在多种组织包括淋巴组织中表达。通过活细胞成像，我们证明在通过B细胞抗原受体（BCR）激活时，TAPP1和TAPP2会被招募到BJAB人类B淋巴瘤细胞的质膜上。C末端的PH结构域对于BCR诱导的TAPP1和TAPP2的膜招募是必要且充分的。阻断磷脂酰肌醇3 - 激酶（PI3K）的活性完全消除了BCR诱导的TAPP1和TAPP2的招募，而活性PI3K的表达足以驱动TAPP1和TAPP2的组成性膜定位。TAPP1和TAPP2优先聚集在质膜的褶皱、富含F - 肌动蛋白的区域，这表明它们在PI3K驱动的细胞骨架重组中具有潜在作用。与Bam32一样，BCR驱动的TAPP1和TAPP2的招募是一种相对缓慢且持续的反应，这与Btk的招募以及Ca²⁺动员反应形成对比，后者是快速且短暂的。与最近的研究表明Bam32、TAPP1和TAPP2能够结合PI(3,4)P₂一致，我们发现膜招募与PI(3,4)P₂的产生密切相关，但与PI(3,4,5)P₃的产生无关。我们的结果表明，TAPP1和TAPP2是PI3K信号传导的直接靶点，它们以独特的延迟动力学被招募到质膜，并聚集在富含F - 肌动蛋白的膜褶皱内。我们推测TAPPs在信号传导的持续阶段起到协调细胞反应的作用。
We report the characterization of two signal transduction proteins related to Bam32, known as TAPP1 and TAPP2. Bam32, TAPPI, and TAPP2 share several characteristics, including small size (32 to 47 kDa), lack of enzymatic domains, high conservation between humans and mice, and the presence of pleckstrin homology (PH) domains near their C termini which contain the 3-phosphoinositide-binding motif. Unlike Bam32, the N-terminal regions of TAPP1 and TAPP2 contain a second PH domain. TAPP1 and TAPP2 transcripts are expressed in a variety of tissues including lymphoid tissues. Using live-cell imaging, we demonstrate that TAPPI and TAPP2 are recruited to the plasma membrane of BJAB human B-lymphoma cells upon activation through the B-cell antigen receptor (BCR). The C-terminal PH domain is necessary and sufficient for BCR-induced membrane recruitment of both TAPP1 and TAPP2. Blockade of phosphatidylinositol 3-kinase (PI3K) activity completely abolished BCR-induced recruitment of TAPP1 and TAPP2, while expression of active PI3K is sufficient to drive constitutive membrane localization of TAPP1 and TAPP2. TAPP1 and TAPP2 preferentially accumulate Within ruffled, F-actin-rich areas of plasma membrane, suggesting a potential role in PI3K-driven cytoskeletal reorganization. Like Bam32, BCR-driven TAPPI and TAPP2 recruitment is a relatively slow and sustained response, in contrast to Btk recruitment and Ca2+ mobilization responses, which are rapid and transient. Consistent with recent studies indicating that Bam32, TAPP1, and TAPP2 can bind to PI(3,4)P-2, We find that membrane recruitment correlates well with production of PI(3,4)P2 but not With that of PI(3,4,5)P-3,. Our results indicate that TAPP1 and TAPP2 are direct targets of PI3K signaling that are recruited into plasma membranes With distinctive delayed kinetics and accumulate within F-actin-rich membrane ruffles. We postulate that the TAPPs function to orchestrate cellular responses during the sustained phase of signaling.