The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis.

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.

• Authors: Kazutaka Sumita, Yu-Hua Lo, Koh Takeuchi, Miki Senda, Satoshi Kofuji, Yoshiki Ikeda, Jumpei Terakawa, Mika Sasaki, Hirofumi Yoshino, Nazanin Majd, Yuxiang Zheng, Emily Rose Kahoud, Takehiro Yokota, Brooke M Emerling, John M Asara, Tetsuo Ishida, Jason W Locasale, Takiko Daikoku, Dimitrios Anastasiou, Toshiya Senda, Atsuo T Sasaki
• Journal: Molecular cell (Mol Cell) Vol. 61 Issue 2 Pg. 187-98 (Jan 21 2016) ISSN: 1097-4164 [Electronic] United States
• PMID: 26774281 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Mutant Proteins
• Phosphatidylinositol Phosphates
• phosphatidylinositol 5-phosphate
• Guanosine Triphosphate
• Adenosine Triphosphate
• PI5P4Kbeta protein, mouse
• Phosphotransferases (Alcohol Group Acceptor)

Topics

• Adenosine Triphosphate (metabolism)
• Amino Acid Sequence
• Animals
• Carcinogenesis (metabolism, pathology)
• Cell Proliferation
• Crystallography, X-Ray
• Guanosine Triphosphate (metabolism)
• HEK293 Cells
• Humans
• Hydrolysis
• Intracellular Space (enzymology)
• Kinetics
• Mice
• Molecular Sequence Data
• Mutant Proteins (chemistry, metabolism)
• Phosphatidylinositol Phosphates (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• Protein Binding
• Proteomics
• Signal Transduction