Sasaki Atsuo T, Janetopoulos Chris, Lee Susan, Charest Pascale G, Takeda Kosuke, Sundheimer Lauren W, Meili Ruedi, Devreotes Peter N, Firtel Richard A
Section of Cell and Developmental Biology, Division of Biological Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093, USA.
J Cell Biol. 2007 Jul 16;178(2):185-91. doi: 10.1083/jcb.200611138.
Phosphoinositide 3-kinase (PI3K)gamma and Dictyostelium PI3K are activated via G protein-coupled receptors through binding to the Gbetagamma subunit and Ras. However, the mechanistic role(s) of Gbetagamma and Ras in PI3K activation remains elusive. Furthermore, the dynamics and function of PI3K activation in the absence of extracellular stimuli have not been fully investigated. We report that gbeta null cells display PI3K and Ras activation, as well as the reciprocal localization of PI3K and PTEN, which lead to local accumulation of PI(3,4,5)P(3). Simultaneous imaging analysis reveals that in the absence of extracellular stimuli, autonomous PI3K and Ras activation occur, concurrently, at the same sites where F-actin projection emerges. The loss of PI3K binding to Ras-guanosine triphosphate abolishes this PI3K activation, whereas prevention of PI3K activity suppresses autonomous Ras activation, suggesting that PI3K and Ras form a positive feedback circuit. This circuit is associated with both random cell migration and cytokinesis and may have initially evolved to control stochastic changes in the cytoskeleton.
磷脂酰肌醇3激酶（PI3K）γ和盘基网柄菌PI3K通过与Gβγ亚基和Ras结合，经G蛋白偶联受体激活。然而，Gβγ和Ras在PI3K激活中的机制作用仍不清楚。此外，在没有细胞外刺激的情况下PI3K激活的动力学和功能尚未得到充分研究。我们报告称，Gβ缺失细胞表现出PI3K和Ras激活，以及PI3K和PTEN的相互定位，这导致PI(3,4,5)P(3)的局部积累。同步成像分析表明，在没有细胞外刺激的情况下，自主的PI3K和Ras激活同时发生在F-肌动蛋白突起出现的相同位点。PI3K与Ras-鸟苷三磷酸结合的丧失消除了这种PI3K激活，而PI3K活性的抑制则抑制了自主的Ras激活，这表明PI3K和Ras形成了一个正反馈回路。该回路与随机细胞迁移和胞质分裂均相关，可能最初是为了控制细胞骨架的随机变化而进化的。
