title: 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.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sumita
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Lo
authors.affiliation: 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.
authors.forename: Koh
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Senda
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kofuji
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Terakawa
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yoshino
authors.affiliation: Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Majd
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Emily Rose
authors.initials: ER
authors.lastname: Kahoud
authors.affiliation: 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.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Emerling
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Chemistry, Biology & Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Takiko
authors.initials: T
authors.lastname: Daikoku
authors.affiliation: Cancer Metabolism Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.affiliation: 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.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Senda
authors.affiliation: 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.
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D006160:Guanosine Triphosphate / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D042541:Intracellular Space / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D015398:Signal Transduction
chemical_list: D050505:Mutant Proteins; D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; C000608224:PI5P4Kbeta protein, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor)