The Lipid Kinase Pi5p4k Beta Is An Intracellular Gtp Sensor For Metabolism And Tumorigenesis

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 beta, 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 beta 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 beta is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4K beta is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4K beta. The critical role of the GTP-sensing activity of PI5P4K beta in cancer signifies this lipid kinase as a cancer therapeutic target.