PKM2 Maintains the Integrity of the Spindle Assembly Checkpoint

The M2 isoform of pyruvate kinase (PKM2) plays a critical role in the regulation of glycolysis and tumor metabolism. In addition, recent studies have identified nonmetabolic functions of PKM2 in gene transcription via phosphorylation of histone H3 and subsequent activation of genes such as CCND1 (encoding cyclin D1), supporting a role for PKM2 in the G₁–S phase transition. However, it remains unclear whether PKM2 also controls mitotic progression. Jiang and colleagues found that mitosis-specific depletion of PKM2 inhibited kinetochore attachment to spindle microtubules and induced aberrant chromosome segregation in tumor cells, suggesting that PKM2 regulates the mitotic spindle assembly checkpoint (SAC). In support of this idea, PKM2 but not PKM1 interacted with and phosphorylated the SAC protein BUB3 at Tyr207 (Y207) during mitosis. Phosphorylation of BUB3 by PKM2 was necessary for the interaction of BUB3 with Blinkin (also known as cancer susceptibility candidate 5), an SAC protein that mediates recruitment of BUB1 and BUB3 to kinetochores, and was required for kinetochore–microtubule attachment and proper chromosome alignment and segregation. Inhibition of PKM2-driven BUB3 phosphorylation impaired SAC function, resulting in accelerated mitotic exit, induction of aneuploidy, and increased apoptosis in both rapidly proliferating embryonic cells and various types of cancer cells, suggesting that tumor cells may be dependent on elevated PKM2 expression for mitotic progression and cell survival. Indeed, PKM2-mediated phosphorylation of BUB3 Y207 promoted EGFR-induced glioblastoma tumor growth in mice, and high levels of BUB3 Y207 phosphorylation in human glioblastoma and lung adenocarcinoma tissue samples were correlated with mitotic progression and reduced survival. These findings identify an essential nonmetabolic role for PKM2 in maintaining the integrity of chromosome segregation and suggest that dysregulation of this function may contribute to tumorigenesis.

Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell 2013 Dec 5 [Epub ahead of print].