Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435, USA.
Cell Signal. 2011 Dec;23(12):1885-95. doi: 10.1016/j.cellsig.2011.06.017. Epub 2011 Jun 29.
Phospholipase D (PLD) catalyzes the conversion of the membrane phospholipid phosphatidylcholine to choline and phosphatidic acid (PA). PLD's mission in the cell is two-fold: phospholipid turnover with maintenance of the structural integrity of cellular/intracellular membranes and cell signaling through PA and its metabolites. Precisely, through its product of the reaction, PA, PLD has been implicated in a variety of physiological cellular functions, such as intracellular protein trafficking, cytoskeletal dynamics, chemotaxis of leukocytes and cell proliferation. The catalytic (HKD) and regulatory (PH and PX) domains were studied in detail in the PLD1 isoform, but PLD2 was traditionally studied in lesser detail and much less was known about its regulation. Our laboratory has been focusing on the study of PLD2 regulation in mammalian cells. Over the past few years, we have reported, in regards to the catalytic action of PLD, that PA is a chemoattractant agent that binds to and signals inside the cell through the ribosomal S6 kinases (S6K). Regarding the regulatory domains of PLD2, we have reported the discovery of the PLD2 interaction with Grb2 via Y169 in the PX domain, and further association to Sos, which results in an increase of de novo DNA synthesis and an interaction (also with Grb2) via the adjacent residue Y179, leading to the regulation of cell ruffling, chemotaxis and phagocytosis of leukocytes. We also present the complex regulation by tyrosine phosphorylation by epidermal growth factor receptor (EGF-R), Janus Kinase 3 (JAK3) and Src and the role of phosphatases. Recently, there is evidence supporting a new level of regulation of PLD2 at the PH domain, by the discovery of CRIB domains and a Rac2-PLD2 interaction that leads to a dual (positive and negative) effect on its enzymatic activity. Lastly, we review the surprising finding of PLD2 acting as a GEF. A phospholipase such as PLD that exists already in the cell membrane that acts directly on Rac allows a quick response of the cell without intermediary signaling molecules. This provides only the latest level of PLD2 regulation in a field that promises newer and exciting advances in the next few years.
磷脂酶 D（PLD）催化细胞膜磷脂酰胆碱转化为胆碱和磷酸脂酸（PA）。PLD 在细胞中的任务有两个：通过磷脂的转化来维持细胞/细胞内膜的结构完整性，以及通过 PA 和其代谢产物进行细胞信号转导。具体来说，通过其反应产物 PA，PLD 参与了多种生理细胞功能，如细胞内蛋白质运输、细胞骨架动力学、白细胞趋化性和细胞增殖。PLD1 同工型的催化（HKD）和调节（PH 和 PX）结构域已被详细研究，但 PLD2 的传统研究较少，对其调节机制的了解也较少。我们的实验室一直专注于研究哺乳动物细胞中 PLD2 的调节。在过去的几年中，我们在关于 PLD 的催化作用方面报告称，PA 是一种趋化剂，它通过核糖体 S6 激酶（S6K）结合并在细胞内发出信号。关于 PLD2 的调节结构域，我们已经报告了发现 PLD2 通过 PX 结构域中的 Y169 与 Grb2 相互作用，并且进一步与 Sos 结合，导致新的 DNA 合成增加，并通过相邻残基 Y179 相互作用（也与 Grb2 相互作用），从而调节细胞皱襞、白细胞趋化性和吞噬作用。我们还介绍了表皮生长因子受体（EGF-R）、Janus 激酶 3（JAK3）和 Src 的酪氨酸磷酸化的复杂调节作用以及磷酸酶的作用。最近，有证据表明通过发现 CRIB 结构域和 Rac2-PLD2 相互作用，对 PH 结构域的 PLD2 进行了新的调节水平，这对其酶活性产生了双重（正和负）影响。最后，我们回顾了 PLD2 作为鸟苷酸交换因子（GEF）的惊人发现。PLD 等已经存在于细胞膜中的磷脂酶可以直接作用于 Rac，使细胞能够快速做出反应，而无需中间信号分子。这只是在这个领域的最新调节水平，预计在未来几年内会有更新和令人兴奋的进展。
