Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

By Weiwei Yang, Yan Xia, Haitao Ji, Yanhua Zheng, Ji Liang, Wenhua Huang, Xiang Gao, Kenneth D. Aldape, Zhimin Lu. Nature, 2011

1,032 citations recorded by the source corpus.

The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. In contrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect, its non-metabolic functions remain elusive. Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited to the CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation and cyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, β-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces β-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f66a7c266e908929c617ed686e479527c0ecbf79

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Citations in the corpus

Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, positive): “Other nuclear functions of dimeric PKM2 includes the ability to act as a protein kinase, activating transcription of mek5 through phosphorylation of STAT3(Gao et al., 2012) as well as promoting β-catenin translocation, leading to expression of cyclinD1 and c-myc(Yang et al., 2011).”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “Second, PKM2 functions as a transcriptional coactivator for OCT4, HIF-1 α and HIF-2 α , and β -catenin (73–75).”
Wnt signaling in cancer. (2012, background): “2A) (Yang et al. 2011b).”
Metabolic regulation of epigenetics (2012, background): “Alternatively metabolic enzymes may function in these complexes independently of their metabolic activity (Tristan et al., 2011; Yang et al., 2011).”
PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis (2012, positive): “PKM2, a glycolytic enzyme with a key role in the Warburg effect (Christofk et al., 2008a; Mellati et al., 1992), also processes nonmetabolic functions and plays a critical role in regulating gene transcription (Yang et al., 2011).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “Cells Is to Facilitate Anabolic Metabolism Accompanying the resurgence of interest in the metabolic effects of PKM2 have been recent reports on ‘‘non-metabolic’’ functions of PKM2 (Luo et al., 2011; Yang et al., 2011).”
The many faces and functions of β‐catenin (2012, positive): “As a result, b-catenin is stabilized and promotes transcription triggering EMT (Yang et al, 2006).”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “In particular, a number of non-metabolic activities mediated by PKM2 upon translocation to the nucleus have been described, including the transactivation of β-catenin (142) and HIF1 (143).”
Tumor glycolysis as a target for cancer therapy: progress and prospects (2013, background): “PK-M2 acts as a kinase and phosphorylates histone H3 to favor tumorigenesis [54], as a nuclear protein it transactivates β-catenin [55], and as a phosphotyrosine binding protein it interacts with other proteins as well [56].”
Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “Interestingly, PKM2 has also been implicated as a coactivator in the b-catenin-dependent transcriptional program (Yang et al., 2011).”