Cancerous cells maintain an altered metabolic state that dramatically increases the flux of nutrients into synthesizing cellular building blocks, which is essential for rapid cell growth and division. A key enzyme required for this proliferative metabolism is the M2 isoform of pyruvate kinase, called PKM2. PKM2 is found predominantly as a dimer and highly expressed in a multitude of cancer types, with a clear correlation between expression levels and tumor aggressiveness. Knock-down of PKM2 or substitution with the adult PKM1 isoform has been shown to reduce cancer cell proliferation, making PKM2 an important target for better understanding the development, diagnosis, and treatment of cancer. Recent work has revealed new and unexpected activities and interactions of PKM2 that are important for promoting cell proliferation. PKM2 binds to and is stimulated by SAICAR, a purine biosynthesis intermediate, and this interaction is important for cancer cell survival in nutrient-poor environments. PKM2 has also been shown to bind to phosphotyrosine-containing proteins, which stabilize PKM2 in a dimeric state. Interestingly, this dimeric state of PKM2 has been shown to have protein kinase activity, inducing altered transcriptional programs by phosphorylating targets such as histone H1 and H3, prothymosin ?, and STAT3. This proposal aims to uncover the structural basis of PKM2 regulation and substrate specificity. We will use X-ray crystallography to capture PKM2 in complex with SAICAR and phosphorylation targets to reveal how these ligands allosterically influence PKM2 structure and function. The results of this research will help provide a structural framework for understanding how PKM2 participates in stimulating cell proliferation in normal and diseased cells.
The rapid proliferation of cancerous cells relies on a characteristic, hyper-excited metabolism that channels nutrient uptake into synthesizing building blocks for cell growth and division. Understanding how diseased cells alter key metabolic enzymes to establish and maintain highly proliferative states is important for detection, treatment, and prevention of cancer.