Hu Hai, Juvekar Ashish, Lyssiotis Costas A, Lien Evan C, Albeck John G, Oh Doogie, Varma Gopal, Hung Yin Pun, Ullas Soumya, Lauring Josh, Seth Pankaj, Lundquist Mark R, Tolan Dean R, Grant Aaron K, Needleman Daniel J, Asara John M, Cantley Lewis C, Wulf Gerburg M
Division of Hematology and Oncology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), Boston, MA 02215, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
Cell. 2016 Jan 28;164(3):433-46. doi: 10.1016/j.cell.2015.12.042.
The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell's metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.
磷酸肌醇3激酶（PI3K）信号通路调控葡萄糖代谢的多个步骤以及细胞骨架功能，如细胞运动和附着。在此，我们表明PI3K以不依赖AKT的方式直接协调糖酵解与细胞骨架动力学。生长因子或胰岛素刺激PI3K依赖的Rac激活，导致肌动蛋白细胞骨架破坏、丝状肌动蛋白结合的醛缩酶A释放以及醛缩酶活性增加。一致地，PI3K抑制剂而非AKT、SGK或mTOR抑制剂会在醛缩酶催化步骤导致糖酵解显著降低，而激活的PIK3CA突变则有相反作用。这些结果表明PI3K具有主要调节功能，整合上皮细胞的代谢及其形态、形状和功能，协调糖酵解与肌动蛋白重塑的能量密集型动力学。
