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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase γ
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Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase γ

机译：表达组成型活性磷脂酰肌醇3-激酶γ的小鼠白细胞中Rac的负反馈调节

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摘要

Polarization of chemotaxing cells depends on positive feedback loops that amplify shallow gradients of chemoattractants into sharp intracellular responses. In particular, reciprocal activation of phosphatidylinositol 3-kinases (PI3Ks) and small GTPases like Rac leads to accumulation, at the leading edge, of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP3). Mice carrying a "knockin" allele of the G protein-coupled receptor (GPCR)-activated PI3Kγ, encoding a plasma membrane-targeted protein appeared normal, but their leukocytes showed GPCR-uncoupled PIP3 accumulation. In vivo, the mutation increased proliferation and decreased apoptosis, leading to leukocytosis and delayed resolution of inflammation in wound healing. Mutant leukocytes showed significantly impaired directional cell migration in response to chemoattractants. Stimulated mutant macrophages did not polarize PIP3 and showed a shortened Rac activation because of enhanced PI3K-dependent activation of RacGAPs. Together with the finding that chemoattractants stimulate a PIP3-dependent GAP activation in wild-type macrophages, these results identify a molecular mechanism involving PI3K- and RacGAP-dependent negative control of Rac that limits and fine-tunes feedback loops promoting cell polarization and directional motility.
机译：趋化细胞的极化取决于正反馈回路，该回路将趋化因子的浅梯度放大为尖锐的细胞内反应。特别地，磷脂酰肌醇3-激酶（PI3K）和小的GTP酶（如Rac）的相互活化导致PI3K产物磷脂酰肌醇3,4,5-三磷酸（PIP3）的积累。携带由G蛋白偶联受体（GPCR）激活的PI3Kγ的“敲除”等位基因的小鼠看来是正常的，但其白细胞显示出与GPCR无关的PIP3积累。在体内，该突变增加增殖并减少凋亡，导致白细胞增多和伤口愈合中炎症的延迟解决。突变白细胞显示出对趋化因子的响应，定向细胞迁移明显受损。刺激的突变巨噬细胞没有极化PIP3，并且由于增强了PI3K依赖的RacGAPs激活而显示了Rac激活缩短。结合化学趋化剂刺激野生型巨噬细胞中PIP3依赖性GAP活化的发现，这些结果确定了涉及PI3K和RacGAP依赖性Rac负控制的分子机制，该机制限制并微调了反馈环，从而促进了细胞极化和定向运动。

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