SAICAR-mediated PKM2 protein kinase activity is necessary for EGF-induced cancer cell proliferation.
Major finding: SAICAR-mediated PKM2 protein kinase activity is necessary for EGF-induced cancer cell proliferation.
Mechanism: PKM2–SAICAR phosphorylates and activates ERK, which phosphorylates PKM2 and promotes SAICAR binding.
Impact: PKM2–SAICAR protein kinase activity couples metabolic status with proliferation in cancer cells.
Pyruvate kinase isoform M2 (PKM2) is a glycolytic enzyme that is overexpressed in most cancer cells and is thought to play a role in tumor metabolism. However, PKM2 has also been found to translocate to the nucleus, phosphorylate histone H3, and regulate gene expression, suggesting that PKM2 may have nonmetabolic functions in cancer cells. Using purified recombinant PKM2 to identify components necessary to activate its protein kinase activity in vitro, Keller and colleagues found that succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5′-phosphate (SAICAR), an intermediate of de novo purine nucleotide biosynthesis that accumulates in glucose-starved cancer cells, markedly stimulated PKM2-mediated phosphorylation of recombinant H3 and was required for PKM2 nuclear localization, H3 phosphorylation, and MYC expression in cancer cells. PKM2–SAICAR protein kinase activity was inhibited by fructose-1,6-bisphosphate, a glycolysis intermediate that activates PKM2 pyruvate kinase activity, suggesting that PKM2 undergoes a functional switch depending on the metabolic status of the cell. Notably, the PKM2–SAICAR complex phosphorylated over 150 proteins on a human proteome microarray, many of which were cancer-associated protein kinases involved in mitogenic signaling or cell-cycle progression. Consistent with this finding, expression of a SAICAR-insensitive PKM2 mutant or SAICAR depletion inhibited EGF-induced ERK activation in cancer cells. PKM2–SAICAR phosphorylated and activated ERK1, and reciprocal PKM2 phosphorylation by ERK2, previously shown to induce PKM2 protein kinase activity, increased the affinity of PKM2 for SAICAR, suggesting that PKM2–SAICAR and ERK may form a positive feedback regulation loop. Indeed, disruption of this regulatory loop by expression of a SAICAR-insensitive or a nonphosphorylatable PKM2 mutant blocked the magnitude and duration of EGF-stimulated ERK activation and inhibited EGF-stimulated cancer cell proliferation. Together, these findings suggest that the altered metabolism observed in most cancer cells may facilitate a SAICAR-dependent PKM2 functional switch that sustains cell proliferation.