Download MendeleyThe Lipid Kinase PI5P4K beta Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis
Sumita, K., Lo, Y.H., Takeuchi, K., Senda, M., Kofuji, S., Ikeda, Y., Terakawa, J., Sasaki, M., Yoshino, H., Majd, N., Zheng, Y., Kahoud, E.R., Yokota, T., Emerling, B.M., Asara, J.M., Ishida, T., Locasale, J.W., Daikoku, T., Anastasiou, D., Senda, T., Sasaki, A.T.(2016) Mol Cell 61: 187-198
- PubMed: 26774281
- DOI: https://doi.org/10.1016/j.molcel.2015.12.011
- Primary Citation of Related Structures:
3WZZ, 3X01, 3X02, 3X03, 3X04, 3X05, 3X06, 3X07, 3X08, 3X09, 3X0A, 3X0B, 3X0C - PubMed Abstract:
While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4K¦Â, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4K¦Â preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4K¦Â is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4K¦Â is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4K¦Â. The critical role of the GTP-sensing activity of PI5P4K¦Â in cancer signifies this lipid kinase as a cancer therapeutic target.
Organizational Affiliation:
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH?45267,?USA.
