title: PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability.
abstract: Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3,4,5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, such as Bcl-XL, were observed in PTEN-deficient mast cells, and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.
authors.affiliation: Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Furumoto
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charles
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.forename: Wai Hang
authors.initials: WH
authors.lastname: Leung
authors.forename: Sandra
authors.initials: S
authors.lastname: Dillahunt
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sargent
authors.forename: Kevin
authors.initials: K
authors.lastname: Tinsley
authors.forename: Sandra
authors.initials: S
authors.lastname: Odom
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.forename: Todd M
authors.initials: TM
authors.lastname: Wilson
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.forename: Manfred
authors.initials: M
authors.lastname: Kneilling
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002199:Capillary Permeability / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008407:Mast Cells / Q000473:pathology* / Q000502:physiology*; D008415:Mastocytosis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse