PKM2: a new player in the β-catenin game

Evaluation of: Yang W, Xia Y, Ji H et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480(7375), 118-122 (2011). beta-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 beta-catenin has also been observed in cancer cells. This study discloses a new mechanism for the transactivation of beta-catenin upon EGF receptor activation that relies on the binding of beta-catenin to the PKM2 isoform in the nucleus. This interaction requires phosphorylation of beta-catenin on the Y333 residue by c-Src and the PKM2 domain that binds phosphotyrosine. Importantly, the authors demonstrated that EGF-induced transactivation of beta-catenin is necessary for brain tumor growth and that high levels of c-Src activity. Y333 beta-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 beta-catenin transactivation. This nuclear function of PKM2 is shared with other transcription factors such as HIF-1 alpha and OCT4, and highlights the nonmetabolic role of PKM2 during tumorigenesis.