Kim C H, Hangoc G, Cooper S, Helgason C D, Yew S, Humphries R K, Krystal G, Broxmeyer H E
Departments of Microbiology/Immunology and Medicine and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Clin Invest. 1999 Dec;104(12):1751-9. doi: 10.1172/JCI7310.
SHIP has been implicated in negative signaling in a number of hematopoietic cell types and is postulated to downregulate phosphatidylinositol-3-kinase- (PI-3K-) initiated events in diverse receptor signaling pathways. Because PI-3K is implicated in chemokine signaling, we investigated whether SHIP plays any role in cellular responses to chemokines. We found that a number of immature and mature hematopoietic cells from SHIP-deficient mice manifested enhanced directional migration (chemotaxis) in response to the chemokines stromal cell-derived factor-1 (SDF-1) and B-lymphocyte chemoattractant (BLC). SHIP(-/-) cells were also more active in calcium influx and actin polymerization in response to SDF-1. However, colony formation by SHIP-deficient hematopoietic progenitor cell (HPCs) was not inhibited by 13 myelosuppressive chemokines that normally inhibit proliferation of HPCs. These altered biologic activities of chemokines on SHIP-deficient cells are not caused by simple modulation of chemokine receptor expression in SHIP-deficient mice, implicating SHIP in the modulation of chemokine-induced signaling and downstream effects.
SHIP已被证实参与多种造血细胞类型的负向信号传导，并被推测可下调磷脂酰肌醇-3激酶（PI-3K）在不同受体信号通路中引发的事件。由于PI-3K与趋化因子信号传导有关，我们研究了SHIP在细胞对趋化因子的反应中是否发挥作用。我们发现，来自SHIP缺陷小鼠的许多未成熟和成熟造血细胞在对趋化因子基质细胞衍生因子-1（SDF-1）和B淋巴细胞趋化因子（BLC）的反应中表现出增强的定向迁移（趋化作用）。SHIP(-/-)细胞对SDF-1的反应中，钙内流和肌动蛋白聚合也更活跃。然而，SHIP缺陷的造血祖细胞（HPC）的集落形成并未受到13种通常抑制HPC增殖的骨髓抑制趋化因子的抑制。趋化因子对SHIP缺陷细胞的这些改变的生物学活性并非由SHIP缺陷小鼠中趋化因子受体表达的简单调节引起，这表明SHIP参与了趋化因子诱导的信号传导和下游效应的调节。
