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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109035-09
Application #
8849293
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2004-07-01
Project End
2017-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
9
Fiscal Year
2015
Total Cost
$266,292
Indirect Cost
$97,753
Name
University of Texas MD Anderson Cancer Center
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Qian, Xu; Li, Xinjian; Tan, Lin et al. (2018) Conversion of PRPS Hexamer to Monomer by AMPK-Mediated Phosphorylation Inhibits Nucleotide Synthesis in Response to Energy Stress. Cancer Discov 8:94-107
Yang, Weiwei; Xia, Yan; Cao, Yu et al. (2018) EGFR-Induced and PKC? Monoubiquitylation-Dependent NF-?B Activation Upregulates PKM2 Expression and Promotes Tumorigenesis. Mol Cell 69:347
Lee, Jong-Ho; Liu, Rui; Li, Jing et al. (2018) EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation. Mol Cell 70:197-210.e7
Lu, Zhimin; Hunter, Tony (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci 43:301-310
Xia, Yan; Yang, Weiwei; Fa, Ming et al. (2017) RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis. J Exp Med 214:1843-1855
Lee, Jong-Ho; Liu, Rui; Li, Jing et al. (2017) Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun 8:949
Wang, Yugang; Guo, Yusong R; Liu, Ke et al. (2017) KAT2A coupled with the ?-KGDH complex acts as a histone H3 succinyltransferase. Nature 552:273-277
Li, Xinjian; Yu, Willie; Qian, Xu et al. (2017) Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Mol Cell 66:684-697.e9
Qian, Xu; Li, Xinjian; Cai, Qingsong et al. (2017) Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy. Mol Cell 65:917-931.e6
Li, Xinjian; Qian, Xu; Peng, Li-Xia et al. (2016) A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol 18:561-71

Showing the most recent 10 out of 44 publications