Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
Immunol Rev. 2009 Nov;232(1):255-72. doi: 10.1111/j.1600-065X.2009.00838.x.
Signaling via phosphoinositide 3-kinases (PI3Ks) has emerged as a central component of lymphocyte activation via immunoreceptors, costimulatory receptors, cytokine receptors, and chemokine receptors. The discovery of phosphoinositide-binding pleckstrin homology (PH) domains has substantially increased understanding of how PI3Ks activate cellular responses. Accumulating evidence indicates that PH-domain containing adapter molecules provide important links between PI3K and lymphocyte function. Here, we review data on PI3K-regulated adapter proteins of the Grb-associated binder (GAB), Src kinase-associated phosphoprotein (SKAP), and B-lymphocyte adapter molecule of 32 kDa (Bam32)/ dual-adapter for phosphotyrosine and 3-phosphoinositides (DAPP)/TAPP families, with a focus on the latter group. Current data support the model that recruitment of these adapters to the plasma membrane of activated lymphocytes is driven by the phosphoinositides phosphatidylinositol-3,4,5-tris-phosphate and phosphatidylinositol-3,4-bisphosphate, generated through the action of PI3Ks and under the regulatory control of lipid phosphatases Src homology 2 domain-containing inositol phosphatase (SHIP), phosphatase and tensin homolog, and inositol polyphosphate 4-phosphatase. At the plasma membrane, these adapters serve to assemble distinct protein complexes. Bam32/DAPP1 and SKAPs function to promote activation of monomeric guanosine triphosphatases, including Rac and Rap, and promote integrin activation, lymphocyte adhesion to matrix proteins, and cell:cell interactions between B and T lymphocytes. GABs can provide feedforward amplification or feedback inhibition of PI3K signaling. Current work is further defining the molecular interactions driven by these molecules and identifying the functions of TAPP adapters, which also appear to be involved in lymphocyte adhesion and are specific effectors downstream of the SHIP product phosphatidylinositol-3,4-bisphosphate.
通过免疫受体、共刺激受体、细胞因子受体和趋化因子受体，磷酸肌醇 3-激酶 (PI3K) 的信号转导已成为淋巴细胞激活的核心组成部分。磷酸肌醇结合pleckstrin 同源 (PH) 结构域的发现大大提高了我们对 PI3K 如何激活细胞反应的理解。越来越多的证据表明，PH 结构域包含的衔接分子为 PI3K 与淋巴细胞功能之间提供了重要的联系。在这里，我们回顾了关于 Grb 相关结合蛋白 (GAB)、Src 激酶相关磷酸蛋白 (SKAP) 和 32kDa B 淋巴细胞衔接分子 (Bam32)/双衔接物用于磷酸酪氨酸和 3-磷酸肌醇 (DAPP)/TAPP 家族的 PI3K 调节衔接蛋白的资料，重点介绍后一组。目前的数据支持这样一种模型，即这些衔接蛋白被募集到激活淋巴细胞的质膜，是由 PI3K 作用下生成的磷酸肌醇-3,4,5-三磷酸和磷酸肌醇-3,4-二磷酸驱动的，其活性受脂质磷酸酶Src 同源 2 结构域含肌醇磷酸酶 (SHIP)、磷酸酶和张力蛋白同系物以及肌醇多磷酸 4-磷酸酶的调节控制。在质膜上，这些衔接物用于组装不同的蛋白质复合物。Bam32/DAPP1 和 SKAPs 用于促进单体鸟苷三磷酸酶（包括 Rac 和 Rap）的激活，并促进整合素激活、淋巴细胞与基质蛋白的黏附以及 B 和 T 淋巴细胞之间的细胞:细胞相互作用。GAB 可以提供 PI3K 信号的前馈放大或反馈抑制。目前的工作进一步定义了这些分子驱动的分子相互作用，并确定了 TAPP 衔接蛋白的功能，这些蛋白似乎也参与了淋巴细胞的黏附，并且是 SHIP 产物磷酸肌醇-3,4-二磷酸下游的特异性效应物。
