Nat. Cell Biol. 14, 1295–1304 (2012)

Credit: NATURE CELL BIOLOGY

The Warburg effect, or aerobic glycolysis, facilitates tumor cell growth. Pyruvate kinase M2 (PKM2) and PKM1 are glycolytic enzymes with overlapping but distinct roles in tumorigenesis that are only partially understood. Both enzymes are active in glucose metabolism, but PKM2 is also a transcriptional coactivator; the relationship between this latter activity of PKM2 and tumorigenesis is unclear. Yang et al. now show that PKM2 translocates to the nucleus in response to EGFR signaling. Small-molecule inhibition of kinases downstream of EGFR showed that only inhibition of MEK-ERK blocked nuclear translocation of PKM2. The authors showed that ERK phosphorylates PKM2 but not PKM1 and that phosphorylation by ERK at Ser37 is important for nuclear translocation of PKM2. Phosphorylation at Ser37 promoted the association of PKM2 with the peptidyl-prolyl isomerase PIN1, and catalytically active PIN1 was required for nuclear translocation of PKM2. In the nucleus, PKM2 promoted association of its cofactor β-catenin with the MYC promoter and affected c-Myc–dependent expression of downstream genes. Genetic depletion of PKM2 reduced glucose consumption and lactate production, indicators of the Warburg effect. Taken together, these data indicate that ERK-dependent phosphorylation, isomerization and nuclear translocation of PKM2 are necessary for the EGFR-dependent Warburg effect.