Further studies revealed that ?-6PGL, but not ?-6GL, promotes Src-PP2A association, probably by binding to Src but not PP2A and enhancing PP2A recruitment. Thus, ?-6PGL is relatively stable compared to ?-6GL but does not participate in oxiPPP. There are two forms of 6PGL, ?-6-phosphogluconolactone (?-6PGL) is an oxiPPP byproduct with unknown function that is generated through intramolecular rearrangement of ?-6-phosphogluconolactone (?-6GL), while ?-6PGL is the only substrate of PGLS and can undergo quick spontaneous hydrolysis. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6PGL level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. In contrast, knockdown of 6PGD or PGLS reduced PP2A activity. Interestingly, we found that knockdown of G6PD did not alter AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. We recently reported that 6PGD is commonly activated by lysine acetylation in cancer cells and activates lipogenesis through controlling its product Ru-5-P, which inhibits the LKB1-AMPK pathway by disrupting the active LKB1 complex (Shan et al., 2014 Mol Cell Lin et al., 2015, Nat Cell Biol.). The third enzyme 6-phosphogluconate dehydrogenase (6PGD) converts 6PG to ribulose-5-phosphate (Ru-5-P) and also produces NADPH. The second enzyme 6-phosphogluconolactonase (PGLS) converts 6PGL to 6-phosphogluconate (6PG). The first enzyme glucose-6-phosphate dehydrogenase (G6PD) converts glycolytic intermediate glucose-6-phosphate (G6P) to 6-phosphogluconolactone (6PGL) and produces NADPH. There are three key enzymes along the oxiPPP. The oxidative pentose phosphate pathway (oxiPPP) plays a crucial role in the metabolic coordination of glycolysis, biosynthesis and redox homeostasis in cells by producing precursors for nucleotide and lipid biosynthesis, as well as antioxidant NADPH that quenches the reactive oxygen species (ROS) produced during rapid proliferation of cancer cells. The interplay between metabolic pathways and cell signaling networks that contribute to the ?metabolic reprogramming? in cancer cells remains largely unknown.
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