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

Mol Cell. 2016 Jan 21;61(2):187-98. doi: 10.1016/j.molcel.2015.12.011.

Kazutaka Sumita ¹, Yu-Hua Lo ², Koh Takeuchi ³, Miki Senda ², Satoshi Kofuji ¹, Yoshiki Ikeda ¹, Jumpei Terakawa ⁴, Mika Sasaki ¹, Hirofumi Yoshino ¹, Nazanin Majd ⁵, Yuxiang Zheng ⁶, Emily Rose Kahoud ⁷, Takehiro Yokota ³, Brooke M Emerling ⁶, John M Asara ⁷, Tetsuo Ishida ⁸, Jason W Locasale ⁹, Takiko Daikoku ⁴, Dimitrios Anastasiou ¹⁰, Toshiya Senda ¹¹, Atsuo T Sasaki ¹²

Affiliations

1 Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
2 Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
3 Biomedicinal Information Research Center and Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto, Tokyo 135-0064, Japan.
4 Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5 Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
6 Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
7 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
8 Department of Chemistry, Biology & Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
9 Department of Pharmacology and Cancer Biology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
10 Cancer Metabolism Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
11 Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan; Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University of Advanced Studies (Soken-dai), Tsukuba, Ibaraki 305-0801, Japan. Electronic address: toshiya.senda@kek.jp.
12 Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Department of Cancer Biology and Department of Neurosurgery, University of Cincinnati College of Medicine, Brain Tumor Center at University of Cincinnati Neuroscience Institute, Cincinnati, OH 45267, USA. Electronic address: atsuo.sasaki@uc.edu.

PMID: 26774281 DOI: 10.1016/j.molcel.2015.12.011

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.

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