Our lab is interested in understanding the molecular mechanisms that control cellular metabolism, particularly in cancer. How do signaling pathways in cancer cells reprogram metabolism to drive growth and proliferation? What are the metabolic bottlenecks of cancer cell growth? How do cells sense key nutrients and other small molecules (metabolites) involved in cellular metabolism? Answering these questions will help us develop a comprehensive map of the connections between signaling pathways and metabolic networks and identify nutrient and metabolic vulnerabilities of cancer cells. These findings have the potential to reveal new therapeutic strategies for cancer and other metabolic disorders.
The role of cellular reducing power in physiology and disease
Metabolite and nutrient sensing by signaling pathways
Identification of novel links between oncogenic kinase signaling and cancer metabolism
Fundamental understanding of the role of cellular reducing power in physiology and disease
Cellular reducing power, which is stored in pyridine nucleotide cofactors NAD(H) and its phosphorylated form NADP(H), drives more than 500 biochemical reactions, including ATP generation, biosynthesis of macromolecules, and redox homeostasis. Dysregulation of cellular reducing power has been linked to many diseases, including cancer. However, the underlying mechanisms of this dysregulation are not well understood.
Recently, we identified the oncogenic PI3K-Akt pathway as a critical regulator of the cellular reducing power through direct stimulation of NAD+ kinase (NADK) (Hoxhaj et al., Science 2019). NADK catalyzes the phosphorylation of NAD+ to NADP+, which is then used to generate NADPH. Despite its importance, the mechanistic regulation of NADK and its cellular and metabolic functions are grossly understudied. Furthermore, the role of NADK in normal tissues and in cancer cells remains poorly defined.
Our laboratory is interested in identifying new regulators of NADK function and cellular reducing power in cancer. We employ quantitative metabolomics, biochemistry, proteomics, and mouse models to obtain a holistic understanding of the regulation of cellular reducing power in physiology and disease. Elucidating the pathways that control cellular redox in cancer could reveal new liabilities that can be exploited for cancer therapies.
Metabolite and nutrient sensing by signaling pathways
The ability to sense metabolites and nutrients is one of the most fundamental properties of all organisms and cells, that has allowed for the adaptation, survival and thriving of species in different environmental and cellular conditions. Metabolite-sensing systems allow for proper communication and calibration of cellular signaling and metabolic status. A classic example is the ability of the protein kinase mTORC1 to sense and integrate signals from growth factors, cellular amino acid levels, and energy status to couple anabolic processes with nutrient and energy availability. In addition to the aforementioned inputs, we recently discovered that adenine nucleotides can also be sensed by mTORC1, but the key sensor(s) that relay this information remain to be identified (Hoxhaj et al., Cell Reports 2017).
Our laboratory is interested in studying how cells sense key metabolites and nutrients. We seek fundamental insights into how nutrient availability and metabolite sensing are coordinated with signaling networks for metabolic control, not only in physiological settings, but also in disease settings, where such coordination is lost.
Identification of novel mechanistic links between oncogenic kinase signaling and cancer metabolism
Rewiring of cellular metabolism is a hallmark of cancer, yet only a handful of metabolic enzymes are known to be mutated in cancer. While much work has been done in recent years to unravel the mechanisms leading to such metabolic alterations, we still have a limited understanding of the oncogenic events that reprogram metabolism in cancer cells.
Work in the past decade has revealed that signaling networks, which are frequently mutated in cancer, can recalibrate cellular metabolism to meet the anabolic demands of cancer cell proliferation (Hoxhaj and Manning, Nat Rev Cancer 2019). Protein kinases are key regulators of signal transduction with vast roles in orchestrating cellular processes, including metabolism. However, out of the 518 kinases in the human kinome, only a small fraction has been implicated in regulating metabolism. Our lab is interested in identifying key kinases that control cancer metabolism. Discovering critical regulatory nodes at the intersection of the kinome and cellular metabolism has the potential to reveal new therapeutic targets.
About Dr. Hoxhaj
Gerta Hoxhaj received her bachelor’s degree from Bogazici University, Istanbul, Turkey, with a double major in molecular biology and genetics and chemistry. She earned her Ph.D. in biochemistry and cell signaling from the MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Scotland, UK, where she characterized a novel E3 ubiquitin ligase, ZNRF2, as a downstream effector of PI3K signaling. In 2013, Dr. Hoxhaj joined the laboratory of Dr. Brendan Manning at the Harvard School of Public Health, where she worked on understanding how oncogenic signaling influences cellular metabolism. Her work discovered new mechanisms that link PI3K-Akt-mTORC1 signaling with the control of nucleotide and redox metabolism.
In 2019, Dr. Hoxhaj joined the faculty of Children’s Medical Center Research Institute at UT Southwestern and became a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar. She holds secondary appointments in the departments of pediatrics and biochemistry at UT Southwestern.
Hoxhaj, G.,* and Manning, B.D.* (2019). The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 116, 2539-2544. (PubMed) *co-corresponding author
Hoxhaj, G., Ben-Sahra, I., Lockwood, S.E., Timson, R.C., Byles, V., Henning, G.T., Gao, P., Selfors, L.M., Asara, J.M., and Manning, B.D. (2019). Direct stimulation of NADP+ synthesis through Akt-mediated phosphorylation of NAD kinase. Science 363, 1088-1092. (PubMed)
Hoxhaj, G., Hallett, J.H., Timson, R., Ilagan, E., Asara, J.M., Ben-Sahra, I., and Manning, B.D. (2017). The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Reports 21,1331-1346. (PubMed)
Ben-Sahra, I.*, Hoxhaj, G.*, Ricoult, S.J., Asara, J.M., and Manning B.D. (2016). mTORC1 induces de Novo Purine Synthesis Through Control of the Mitochondrial Tetrahydrofolate Cycle. Science 351, 728-33. (PubMed) *co-first author
Hoxhaj, G.*, Caddye, E., Najafov, A., Houde, V.P., Johnson, C., Dissanayake, K., Toth, R., Campbell, D.G., Prescott, A.R., and MacKintosh, C.* (2016). The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids. eLife pii: e12278. (PubMed) *co-corresponding author
Hoxhaj, G.*, Najafov, A., Toth, R., Campbell, D.G., Prescott, A.R., and MacKintosh, C.* (2012). ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase. J Cell Science 125, 4662-75. (PubMed) *co-corresponding author