The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis
More about Open Access at the CrickAuthors list
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 SasakiAbstract
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.
Journal details
Journal Molecular Cell
Volume 61
Issue number 2
Pages 187-198
Available online
Publication date
Full text links
Publisher website (DOI) 10.1016/j.molcel.2015.12.011
Figshare View on figshare
Europe PubMed Central 26774281
Pubmed 26774281
Keywords
Related topics
Type of publication