Targeted disruption of SHIP leads to Steel factor-induced degranulation of mast cells
Targeted disruption of SHIP leads to Steel factor-induced degranulation of mast cells
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DOI：
10.1093/emboj/17.24.7311
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发表时间：
1998-12-15
期刊：
影响因子：
11.4
通讯作者：
Krystal, G
中科院分区：
文献类型：
--
作者：
Huber, M;Helgason, CD;Krystal, G
为了研究含有 src 同源性 2 (SH2) 的肌醇 5' 磷酸酶 (SHIP) 在生长因子介导的信号传导中的作用，我们比较了 SHIP-/- 和 SHIP+/+ 同窝小鼠的骨髓源性肥大细胞 (BMMC) 中钢因子 (SF) 诱导的事件，我们发现 SF 单独刺激 SHIP-/- 的大量脱颗粒，但不刺激 SHIP+/+ BMMC 的大量脱颗粒，这种 SF 诱导的脱颗粒并非由于 SHIP-/- 细胞中较高的 c-kit 水平所致，与细胞内钙含量高于 SHIP+/+ 细胞相关，并且依赖于细胞外钙的流入。这种流入和随后的脱颗粒均被 PI-3-激酶抑制剂完全抑制，表明 SF 诱导的 PI-3-激酶激活位于细胞外钙进入的上游。 SF 刺激 SHIP+/+ 和 SHIP-/- BMMC 后磷脂酰肌醇-3,4,5-三磷酸 (PIP3) 水平表明 SHIP 通过水解 PIP3 限制这种进入，尽管 PI-3-激酶抑制剂阻止细胞内钙的释放，暗示 PIP3，并且 PLC gamma-2 在 SHIP-/- 细胞中酪氨酸磷酸化程度稍高，但SHIP-/- 和 SHIP+/+ BMMC 中肌醇-1,4,5-三磷酸 (IP3) 和细胞内钙水平相同。这些结果表明，SHIP 通过水解 PIP3 阻止 SF 触发正常 BMMC 脱粒，从而在细胞内钙释放后的一步限制细胞外钙进入。
To investigate the role of the src homology 2 (SH2)-containing inositol 5' phosphatase (SHIP) in growth factor-mediated signalling, we compared Steel factor (SF)-induced events in bone marrow-derived mast cells (BMMCs) from SHIP-/- and SHIP+/+ littermates, We found SF alone stimulated massive degranulation from SHIP-/- but none from SHIP+/+ BMMCs, This SF-induced degranulation, which was not due to higher c-kit levels in SHIP-/- cells, correlated with higher intracellular calcium than that in SHIP+/+ cells and was dependent on the influx of extracellular calcium, Both this influx and subsequent degranulation were completely inhibited by PI-3-kinase inhibitors, indicating that SF-induced activation of PI-3-kinase was upstream of extracellular calcium entry, A comparison of phosphatidylinositol-3,4,5-trisphosphate (PIP3) levels following SF stimulation of SHIP+/+ and SHIP-/- BMMCs suggested that SHIP restricted this entry by hydrolyzing PIP3, Although PI-3-kinase inhibitors blocked the release of intracellular calcium, implicating PIP3, and PLC gamma-2 was slightly more tyrosine phosphorylated in SHIP-/- cells, the increase in inositol-1,4,5-trisphosphate (IP3) and intracellular calcium levels were identical in SHIP-/- and SHIP+/+ BMMCs, These results suggest that SHIP prevents SF from triggering degranulation of normal BMMCs, and does so by hydrolyzing PIP3, which in turn limits extracellular calcium entry at a step after the release of intracellular calcium.