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)P₃) regulate cell migration, but the role of PtdIns(3,4,5)P₃-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)P₃ 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)P₃ phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)P₃ 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)P₃ accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.

1. Department of Pathology and Immunology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010–8543, Japan.
2. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332–0012, Japan.
3. Department of Molecular Biology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010–8543, Japan.
4. Department of Laboratory Animal Science, the Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113–8613, Japan.
5. Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
6. Department of Pharmacology, the Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113–8613, Japan.
7. Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010–8543, Japan.
8. Institut für Umweltmedizinische Forschung, University of Düsseldorf, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
9. Campbell Family Institute for Breast Cancer Research, 620 University Ave., Suite 706, Toronto, Ontario, Canada M5G 2C1.
10. Institute of Molecular and Biotechnology of the Austrian Academy of Sciences, Dr Bohr-Gasse 3, A-1030 Vienna, Austria.
11. These authors contributed equally to this work.

Correspondence to: Takehiko Sasaki^1,2,11 e-mail: tsasaki@med.akita-u.ac.jp

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