Lu Z.

Summary:
Pyruvate kinase catalyzes the rate-limiting final step of glycolysis, generating adenosine triphosphate(ATP) and pyruvate. The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptakeand lactate production in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. Asrecently reported in Nature, PKM2, besides its metabolic function, has a nonmetabolic function in thedirect control of cell cycle progression by activating β-catenin and inducing expression of the β-catenindownstream gene CCND1 (encoding for cyclin D1). This nonmetabolic function of PKM2 is essential forepidermal growth factor receptor (EGFR) activation-induced tumorigenesis.

Yang W, Xia X, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z.

Summary:
The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. Incontrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect1,2,3, itsnonmetabolic functions remain elusive. Here we demonstrate that EGFR activation inducestranslocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Srcphosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited tothe CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation, andcyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFRpromotedtumor cell proliferation and brain tumor development. In addition, positive correlationshave been identified among c-Src activity, β-catenin Y333 phosphorylation, and PKM2 nuclearaccumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylationand nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. Thesefindings reveal that EGF induces β-catenin transactivation via a mechanism distinct from thatinduced by Wnt/wingless4 and highlight the essential nonmetabolic functions of PKM2 in EGFRpromotedβ-catenin transactivation, cell proliferation, and tumorigenesis.

Figure 5: A mechanism for EGFR-induced β-catenin transactivation

Lu Z.