The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis

By Kazutaka Sumita, Y. Lo, K. Takeuchi, M. Senda, Satoshi Kofuji, Y. Ikeda, Jumpei Terakawa, Mika Sasaki, H. Yoshino, N. Majd and 11 more. 2016

67 citations recorded by the source corpus.

Summary 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.

Subfields: Cancer Research, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Lewis C. Cantley
2. M. V. Vander Heiden
3. Craig B. Thompson

In Molecular Biology

1. Lewis C. Cantley
2. Nathanael S. Gray
3. David M. Sabatini
4. M. Laplante
5. M. V. Vander Heiden
6. J. Engelman
7. P. Pandolfi
8. Craig B. Thompson

Citations in the corpus

• Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors (2020, background): “Notably, the Phe205 residue that engages in aromatic p-stacking interactions with the phenylenediamine moiety of THZ-P1-2 is conserved among the PI5P4Ks and has been identified as the residue responsible for the GTP-sensing ability of PI5P4KP (Sumita et al., 2016).”