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 PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kβ 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 PI5P4Kβ is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kβ is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kβ. The critical role of the GTP-sensing activity of PI5P4Kβ in cancer signifies this lipid kinase as a cancer therapeutic target.
Highlights
We set out to identify a protein that would meet the requirements for the guanosine triphosphate (GTP) sensor, and we discovered a GTP sensor, Phosphatidylinositol 5-phosphate 4-kinase b (PI5P4Kb), which converts GTP concentration cues into phosphatidylinositol 5-phosphate (PI(5)P) second messenger signaling and tumorigenesis
Proteomic Screen Identifies PI5P4Ks as GTP-Binding Proteins To identify a candidate for the GTP sensor, we performed a proteomic screening for signaling proteins that have an ability to bind to GTP
We found that PI5P4Kb in cell extracts bound to the GTP-conjugated agarose beads more strongly than to the adenosine triphosphate (ATP)-conjugated agarose beads, which verified the result of the proteomic screening
Summary
Sensing cellular energy status is fundamental to all organisms. Lo, and Takeuchi et al identified PI5P4Kb as an energy sensor that couples cellular GTP concentration with lipid second messenger signaling. The GTP-sensing mechanism will change the current homeostasis model and represents a target for cancer therapeutics. Highlights d Cellular GTP concentration functions as a biological cue via a GTP sensor, PI5P4Kb d PI5P4Kb kinase activity converts the GTP cue into PI(5)P second messenger signaling d The GTP-sensing activity of PI5P4Kb is critical for tumorigenesis d GTP-sensing activity of PI5P4Kb represents a target for cancer therapeutics.
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