Fig. 4

ERK- and JNK-mediated phosphorylation of PKM2 is at the crossroad between proliferation and apoptosis. PKM2 acts as master regulator of the Warburg effect. Of the many posttranslational modifications, phosphorylation of PKM2 by either ERK or JNK1 dictates distinct outcomes. In quiescent cells, PKM2 is present as a tetrameric protein associated with elevated enzymatic activity. When cells receive a growth stimulus, activation of ERK drives phosphorylation of tetrameric PKM2. Phosphorylated PKM2 is then cis-trans isomerized by PIN1 allowing dissociation of tetrameric PKM2 to monomers. Monomeric PKM2 enters the nucleus where it acts as histone-binding protein allowing gene expression regulation of both glycolytic enzymes and cell cycle regulators (i.e., c-Myc, cyclin D1). Besides, accumulation of reactive oxygen species (ROS) in the cytoplasm promotes activation of JNK1, which can phosphorylate and enhance PKM2 activation, allowing cells to reduce their antioxidant capacity and induce apoptosis. Notably, enhanced expression of PARP14 in cancer cells suppresses JNK1-mediated phosphorylation and activation of PKM2, providing therefore survival advantages to cancer cells. PARP14 by suppressing JNK1 activity contributes to maintain low PKM2 activity and, combined with a robust glycolysis, leads to an accumulation of glycolytic intermediates, including precursors of nucleic acids, lipids, and amino acids. This accumulation provides a metabolic bottleneck allowing glycolytic intermediates to be redirected toward biosynthesis, fueling through the pentose phosphate pathway for DNA synthesis and thereby contributing to the rapid cell proliferation seen in tumors