The scaffolding adapter Gab2, via Shp-2, regulates kit-evoked mast cell proliferation by activating the Rac/JNK pathway
The scaffolding adapter Gab2, via Shp-2, regulates kit-evoked mast cell proliferation by activating the Rac/JNK pathway
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DOI：
10.1074/jbc.m603742200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Gu, Haihua
中科院分区：
文献类型：
--
作者：
Yu, Min;Luo, Jincai;Gu, Haihua
支架接头 Gab2 介导细胞信号传导和由多种细胞外刺激（包括多种生长因子）引起的反应。 Kit 是干细胞因子 (SCF) 的受体，在包括肥大细胞在内的多种细胞类型的增殖和分化中发挥着关键作用。 Kit 通过 Tyr(567) 和 Tyr(719) 分别激活 Src 家族激酶 (SFK) 和 PI3K，这些激酶集中于肥大细胞增殖所需的 Rac/JNK 通路的激活。然而，Kit Tyr(567) 如何向 Rac/JNK 发出信号尚不清楚。通过分析Gab2(-/-)肥大细胞，我们发现Gab2是SCF诱发的增殖、Rac/JNK和Ras激活所必需的。在野生型肥大细胞中 Kit 激活后，Gab2 被酪氨酰磷酸化并与 Kit 和 Shp-2 结合。 Tyr(567)（Kit 中的 SFK 结合位点）和 SFK 活性是 Gab2 酪氨酰磷酸化以及与 Shp-2 关联所必需的。通过在Gab2(-/-)肥大细胞中重新表达Gab2或不能结合Shp-2的Gab2突变体，或通过在肥大细胞中急性删除Shp-2，我们发现Gab2需要Shp-2来促进SCF诱发的Rac/JNK、Ras激活和肥大细胞增殖。最后，通过分析具有复合 Gab2 和 Kit Y719F 突变的小鼠（即 Gab2(-/-)：KitY719F/Y719F 小鼠）的肥大细胞，我们发现 Gab2 与 Kit Tyr(719) 的 PI3K 平行途径起作用，调节特定组织中肥大细胞的增殖和发育。我们的数据表明，Gab2 通过 Shp-2 对于从 Kit Tyr(567) 传输信号以激活控制肥大细胞增殖的 Rac/JNK 途径至关重要，这可能有助于特定组织中肥大细胞的发育。
The scaffolding adapter Gab2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr(567) and Tyr(719), activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr(567) signals to Rac/JNK is not well understood. By analyzing Gab2(-/-) mast cells, we find that Gab2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, Gab2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr(567), an SFK binding site in Kit, and SFK activity were required for Gab2 tyrosyl phosphorylation and association with Shp-2. By re-expressing Gab2 or a Gab2 mutant that cannot bind Shp-2 in Gab2(-/-) mast cells or acutely by deleting Shp-2 in mast cells, we found that Gab2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound Gab2 and Kit Y719F mutations (i.e., Gab2(-/-): KitY719F/Y719F mice), we find that Gab2, acting in a parallel pathway to PI3K from Kit Tyr(719), regulates mast cell proliferation and development in specific tissues. Our data show that Gab2 via Shp-2 is critical for transmitting signals from Kit Tyr(567) to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.