title: In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes.
abstract: The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K-AKT signaling and are frequently dysregulated in human cancer. Although PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor-suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of the PI3K-AKT pathway at the endosomes.
  
  
  CONCLUSIONS
  Although both PTEN and INPP4B can inhibit PI3K-AKT signaling through their lipid phosphatase activities, here we demonstrate lack of an epistatic relationship between the two tumor suppressors. Instead, the qualitative regulation of PI3K-AKT2 signaling by INPP4B provides a mechanism for their cooperation in suppressing thyroid tumorigenesis and metastasis.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Chen
authors.initials: C
authors.lastname: Li Chew
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lunardi
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Gulluni
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michiya
authors.initials: M
authors.lastname: Nishino
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Antonella
authors.initials: A
authors.lastname: Papa
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fung
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine and Research Center for Biosignal, Akita University, Akita, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine and Research Center for Biosignal, Akita University, Akita, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. ppandolf@bidmc.harvard.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D051059:PTEN Phosphohydrolase