A study published in Nature (2011) reveals that the nuclear isoform of pyruvate kinase M2 (PKM2) regulates β-catenin transactivation upon epidermal growth factor receptor (EGFR) activation. PKM2 translocates to the nucleus upon EGFR activation, where it binds to phosphorylated Y333 of β-catenin, facilitating their recruitment to the CCND1 promoter. This interaction leads to histone H3 acetylation, cyclin D1 expression, and enhanced cell proliferation. PKM2-dependent β-catenin transactivation is essential for EGFR-promoted tumor cell proliferation and brain tumor development. The study also shows that c-Src phosphorylates β-catenin at Y333, which is required for PKM2 binding. PKM2's nonmetabolic function in β-catenin transactivation is critical for tumor development, distinct from the Wnt signaling pathway. The study further demonstrates that PKM2's interaction with β-catenin is essential for cyclin D1 expression and cell cycle progression. Analysis of human glioblastoma specimens reveals a correlation between β-catenin phosphorylation, nuclear PKM2 accumulation, and glioma malignancy and prognosis. These findings highlight the essential role of PKM2 in EGFR-induced β-catenin transactivation, cell proliferation, and tumorigenesis. The study also shows that PKM2's interaction with β-catenin is required for histone H3 acetylation and HDAC3 removal from the CCND1 promoter. The results indicate that PKM2's nonmetabolic function in β-catenin transactivation is essential for tumor development, and that PKM2's metabolic function is important for aerobic glycolysis and tumorigenesis. The study provides a molecular basis for improved diagnosis and treatment of tumors with activated EGFR and upregulated PKM2.A study published in Nature (2011) reveals that the nuclear isoform of pyruvate kinase M2 (PKM2) regulates β-catenin transactivation upon epidermal growth factor receptor (EGFR) activation. PKM2 translocates to the nucleus upon EGFR activation, where it binds to phosphorylated Y333 of β-catenin, facilitating their recruitment to the CCND1 promoter. This interaction leads to histone H3 acetylation, cyclin D1 expression, and enhanced cell proliferation. PKM2-dependent β-catenin transactivation is essential for EGFR-promoted tumor cell proliferation and brain tumor development. The study also shows that c-Src phosphorylates β-catenin at Y333, which is required for PKM2 binding. PKM2's nonmetabolic function in β-catenin transactivation is critical for tumor development, distinct from the Wnt signaling pathway. The study further demonstrates that PKM2's interaction with β-catenin is essential for cyclin D1 expression and cell cycle progression. Analysis of human glioblastoma specimens reveals a correlation between β-catenin phosphorylation, nuclear PKM2 accumulation, and glioma malignancy and prognosis. These findings highlight the essential role of PKM2 in EGFR-induced β-catenin transactivation, cell proliferation, and tumorigenesis. The study also shows that PKM2's interaction with β-catenin is required for histone H3 acetylation and HDAC3 removal from the CCND1 promoter. The results indicate that PKM2's nonmetabolic function in β-catenin transactivation is essential for tumor development, and that PKM2's metabolic function is important for aerobic glycolysis and tumorigenesis. The study provides a molecular basis for improved diagnosis and treatment of tumors with activated EGFR and upregulated PKM2.