Pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis, is instrumental for tumorigenesis. In addition to its well-studied role in cell metabolism, PKM2 promotes cell proliferation through an unknown mechanism. Our preliminary data showed that activation of epidermal growth factor (EGF) receptor (EGFR) results in PKM2 nuclear translocation. In addition, nuclear translocated PKM2 interacts with β-catenin and mediates β-catenin–regulated gene transcription. We hypothesize that β-catenin, by interacting with nuclear PKM2, plays an instrumental role in EGFR-promoted tumor development.