CSF-1 receptor signalling from endosomes mediates the sustained activation of Erk1/2 and Akt in Macrophages
CSF-1 receptor signalling from endosomes mediates the sustained activation of Erk1/2 and Akt in Macrophages
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DOI：
10.1016/j.cellsig.2012.04.022
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发表时间：
2012-09-01
影响因子：
4.8
通讯作者：
Scholz, Glen M.
中科院分区：
文献类型：
--
作者：
Huynh, Jennifer;Kwa, Mei Qi;Scholz, Glen M.
集落刺激因子-1 (CSF-1) 通过 CSF-1 受体 (CSF-1R)（一种受体酪氨酸激酶）介导其对巨噬细胞的多效性作用。目前的 CSF-1 信号传导模型表明，CSF-1R 仅激活质膜上的信号传导途径，随后 CSF-1R 的内化只是促进其溶酶体降解，以防止持续的信号传导。在这里，我们试图确定 CSF-1R 实际上是否可以在其内化后继续发出信号。当 CSF-1R 的内化受损时，Erk1/2、Akt 和 Stat3 的激活被消除，对 Stat3 的影响与 Erk1/2 和 Akt 的影响不同。CSF-1R 内化后的药理学抑制导致 Erk1/2 和 Akt 活性的持续性降低，而 Stat3 活性不受影响。值得注意的是，无论是在 CSF-1 刺激之前还是在 CSF-1R 内化之后添加抑制剂，CSF-1R 抑制剂对 CSF-1 基因表达上调（例如细胞周期蛋白 D1 和 Bcl-xL 基因表达）的抑制作用都是相当的。类似地，在 CSF-1 刺激之前或 CSF-1R 内化之后对 Erk1/2（或 Akt）活性的药理抑制对 CSF-1 基因表达的调节具有类似的效果。总之，我们的数据表明，对 CSF-1 的关键信号传导反应取决于 CSF-1R 内化后从内体发出信号的能力，从而为 CSF-1R 信号传导增加了重要的时空方面。 (C) 2012 Elsevier Inc. 保留所有权利。
Colony stimulating factor-1 (CSF-1) mediates its pleiotropic effects on macrophages through the CSF-1 receptor (CSF-1R), a receptor tyrosine kinase. Current models of CSF-1 signalling imply that the CSF-1R activates signalling pathways exclusively at the plasma membrane and the subsequent internalisation of the CSF-1R simply facilitates its lysosomal degradation in order to prevent on-going signalling. Here, we sought to establish if the CSF-1R may in fact continue to signal following its internalisation. Erk1/2, Akt and Stat3 activation were abrogated when the internalisation of the CSF-1R was impaired, with the effects on Stat3 distinct from those for Erk1/2 and Akt Pharmacologic inhibition of the CSF-1R following its internalisation resulted in less sustained Erk1/2 and Akt activity, whereas Stat3 activity was unaffected. Significantly, the suppressive effects of the CSF-1R inhibitor on the up-regulation of gene expression by CSF-1 (e.g. cyclin D1 and Bcl-xL gene expression) were comparable irrespective of whether the inhibitor was added prior to CSF-1 stimulation or following the internalisation of the CSF-1R. Similarly, pharmacologic inhibition of Erk1/2 (or Akt) activity either prior to CSF-1 stimulation or subsequent to CSF-1R internalisation had comparable effects on the regulation of gene expression by CSF-1. Together, our data argue that key signalling responses to CSF-1 depend on the ability of the CSF-1R to signal from endosomes following its internalisation, thus adding an important spatiotemporal aspect to CSF-1R signalling. (C) 2012 Elsevier Inc. All rights reserved.