title: Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1.
abstract: Proper neutrophil migration into inflammatory sites ensures host defense without tissue damage. Phosphoinositide 3-kinase (PI(3)K) and its lipid product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) regulate cell migration, but the role of PtdIns(3,4,5)P(3)-degrading enzymes in this process is poorly understood. Here, we show that Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)P(3) phosphatase, is a key regulator of neutrophil migration. Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility. In contrast, loss of the PtdIns(3,4,5)P(3) phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)P(3) metabolism in living primary cells, we generated a novel transgenic mouse (AktPH-GFP Tg) expressing a bioprobe for PtdIns(3,4,5)P(3.) Time-lapse footage showed rapid, localized binding of AktPH-GFP to the leading edge membrane of chemotaxing ship1(+/+)AktPH-GFP Tg neutrophils, but only diffuse localization in ship1(-/-)AktPH-GFP Tg neutrophils. By directing where PtdIns(3,4,5)P(3) accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.
authors.affiliation: Department of Pathology and Immunology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takasuga
authors.forename: Ryota
authors.initials: R
authors.lastname: Iizuka
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Reietsu
authors.initials: R
authors.lastname: Itoh
authors.forename: Shoko
authors.initials: S
authors.lastname: Kuroda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D002478:Cells, Cultured; D002633:Chemotaxis; D058544:Class Ib Phosphatidylinositol 3-Kinase; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D051058:Oncogene Protein v-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases