Overexpression of epidermal growth factor (EGF) receptor (EGFR) and transactivation of ?-catenin have been detected separately in many human tumors and correlate with a poor clinical prognosis. We recently revealed that EGFR activation induces ?-catenin transactivation in a glycogen synthase kinase-3? (GSK3?)-canonical pathway-independent manner. However, how EGFR-induced signaling regulates nuclear ?-catenin transactivation and thereby promotes tumor progression remains unclear. Pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis, is instrumental for tumorgenesis. In addition to its well-studied role in cell metabolism, PKM2 promotes cell proliferation though an unknown mechanism. Our preliminary data showed that activation of EGFR results in PKM2 nuclear translocation. In addition, nuclear translocated PKM2 interacts with ?-catenin and mediates ?-catenin-regulated gene transcription. We hypothesize that regulation of ?-catenin by interacting with nuclear PKM2 plays an instrumental role in EGFR-promoted tumor development.
In Specific Aim 1, we will determine the mechanisms underlying EGF-induced PKM2 nuclear translocation.
In Specific Aim 2, we will determine whether the interaction between nuclear PKM2 to ?-catenin is essential for EGF-induced ?-catenin transactivation.
In Specific Aim 3, we will differentiate the functions of cytosolic and nuclear PKM2 and determine the role of ?-catenin regulation by PKM2 in EGFR-promoted tumor development. We expect that our proposed research will provide important and previously unrevealed mechanisms of EGFR-promoted tumor development via crosstalking EGFR with Wnt pathways, which are dependent on nonmetabolic functions of PKM2. Building on our findings, therapy strategies targeting EGF-induced ?-catenin regulation may be developed to enhance current EGFR-based cancer therapies.
Overexpression of epidermal growth factor (EGF) receptor (EGFR) has been detected in many human tumors and is correlated with poor clinical prognosis;however, how EGFR-induced signaling promotes tumor progression remains obscure. In this proposed study, our goal is to elucidate the mechanisms of EGF-induced regulation of ?- catenin transactivation thereby inducing downstream gene expression, which plays a pivotal role in tumor development. The experiments described in our proposal may help us identify molecular markers of prognosis and develop more effective cancer therapies.
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|Liang, Ji; Cao, Ruixiu; Zhang, Yajuan et al. (2016) PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nat Commun 7:12431|
|Yang, Weiwei; Lu, Zhimin (2015) Pyruvate kinase M2 at a glance. J Cell Sci 128:1655-60|
|Zheng, Yanhua; Li, Xinjian; Qian, Xu et al. (2015) Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation. Nat Cell Biol 17:1348-55|
|Jiang, Yuhui; Qian, Xu; Shen, Jianfeng et al. (2015) Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol 17:1158-68|
|Jiang, Yuhui; Li, Xinjian; Yang, Weiwei et al. (2014) PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell 53:75-87|
|Lu, Zhimin; Hunter, Tony (2014) Prolyl isomerase Pin1 in cancer. Cell Res 24:1033-49|
|Xue, Junli; Xie, Victoria K; Wang, Peipei et al. (2014) Interrelationships of circulating tumor cells with metastasis and thrombosis: role of microRNAs. Curr Pharm Des 20:5298-308|
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