The study investigates the role of nuclear PKM2 in β-catenin transactivation upon EGFR activation. It demonstrates that EGFR activation induces the nuclear translocation of PKM2, which binds to c-Src-phosphorylated β-catenin at Y333, leading to recruitment to the CCND1 promoter, removal of HDAC3, histone H3 acetylation, and cyclin D1 expression. This PKM2-dependent β-catenin transactivation is crucial for EGFR-promoted tumor cell proliferation and brain tumor development. The study also finds positive correlations between c-Src activity, β-catenin Y333 phosphorylation, and nuclear PKM2 accumulation in human glioblastoma specimens, and these markers are associated with tumor grades and prognosis. These findings highlight the essential nonmetabolic functions of PKM2 in EGFR-induced β-catenin transactivation and tumorigenesis.The study investigates the role of nuclear PKM2 in β-catenin transactivation upon EGFR activation. It demonstrates that EGFR activation induces the nuclear translocation of PKM2, which binds to c-Src-phosphorylated β-catenin at Y333, leading to recruitment to the CCND1 promoter, removal of HDAC3, histone H3 acetylation, and cyclin D1 expression. This PKM2-dependent β-catenin transactivation is crucial for EGFR-promoted tumor cell proliferation and brain tumor development. The study also finds positive correlations between c-Src activity, β-catenin Y333 phosphorylation, and nuclear PKM2 accumulation in human glioblastoma specimens, and these markers are associated with tumor grades and prognosis. These findings highlight the essential nonmetabolic functions of PKM2 in EGFR-induced β-catenin transactivation and tumorigenesis.