Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1
Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1
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DOI：
10.1038/ncb1515
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发表时间：
2007-01-01
影响因子：
21.3
通讯作者：
Sasaki, Takehiko
中科院分区：
文献类型：
--
作者：
Nishio, Miki;Watanabe, Ken-ichi;Sasaki, Takehiko
中性粒细胞适当迁移到炎症部位可确保宿主防御而不损伤组织。磷酸肌醇 3-激酶 (PI(3)K) 及其脂质产物磷脂酰肌醇 3,4,5-三磷酸 (PtdIns(3,4,5)P-3) 调节细胞迁移，但 PtdIns(3,4,5)P-3 降解酶在此过程中的作用知之甚少。在这里，我们发现含有 Src 同源 2 (SH2) 结构域的肌醇 5 磷酸酶 1 (SHIP1)（一种 PtdIns(3,4,5)P-3 磷酸酶）是中性粒细胞迁移的关键调节因子。 SHIP1 的基因失活导致中性粒细胞极化和运动的严重缺陷。相反，PtdIns(3,4,5)P-3 磷酸酶 PTEN 的缺失对中性粒细胞趋化性没有影响。为了研究活原代细胞中的 PtdIns(3,4,5)P-3 代谢，我们制备了表达 PtdIns(3,4,5)P-3 生物探针的新型转基因小鼠 (AktPH-GFP Tg)。延时录像显示 AktPH-GFP 与趋化性 Ship1(+/+)AktPH-GFP Tg 中性粒细胞前缘膜快速、局部结合，但仅在 Ship1(-/-)AktPH-GFP Tg 中性粒细胞中弥散定位。通过引导 PtdIns(3,4,5)P-3 积聚的位置，SHIP1 控制趋化所需的前缘和极化的形成。
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.