title: INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor.
abstract: Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4b(Δ/Δ)) nor heterozygous deletion of Pten (Pten(+/-)) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a "back-up" mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers.
  
  
  CONCLUSIONS
  Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3.
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kofuji
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Department of Pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nanjo
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takasuga
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Reietsu
authors.initials: R
authors.lastname: Itoh
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ueno
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan. Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan. Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Research Center for Biosignal, Akita University, Akita, Japan. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan. tsasaki@med.akita-u.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D051059:PTEN Phosphohydrolase