PKM2: a new player in the β-catenin game

β-catenin is a key player in the regulation of gene expression during morphogenesis and tumorigenesis. Although its transactivation often results from stimulation of the Wnt signaling pathway, Wnt-independent regulation of β-catenin has also been observed in cancer cells. This study discloses a new mechanism for the transactivation of β-catenin upon EGF receptor activation that relies on the binding of β-catenin to the PKM2 isoform in the nucleus. This interaction requires phosphorylation of β-catenin on the Y333 residue by c-Src and the PKM2 domain that binds phosphotyrosine. Importantly, the authors demonstrated that EGF-induced transactivation of β-catenin is necessary for brain tumor growth and that high levels of c-Src activity, Y333 β-catenin phosphorylation and nuclear localization of PKM2 altogether correlate with high aggressiveness of tumors in glioblastoma multiforme. Remarkably, this study reveals a novel role for PKM2 in cancer cells where PKM2 appears to be, in addition to its established role in aerobic glycolysis, a major coactivator of β-catenin transactivation. This nuclear function of PKM2 is shared with other transcription factors such as HIF-1α and OCT4, and highlights the nonmetabolic role of PKM2 during tumorigenesis.