Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling.
Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling.
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DOI：
10.1016/j.devcel.2023.11.023
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发表时间：
2023-12
影响因子：
11.8
通讯作者：
Joanne E. Simpson;Morwenna T. Muir;Martin Lee;C. Naughton;Nick Gilbert;Steven M Pollard;Noor Gammoh-Noor
中科院分区：
文献类型：
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作者：
Joanne E. Simpson;Morwenna T. Muir;Martin Lee;C. Naughton;Nick Gilbert;Steven M Pollard;Noor Gammoh-Noor
自噬是一种保守的细胞降解过程。虽然与自噬相关的蛋白被证明影响某些受体酪氨酸激酶的信号和运输，但这种影响在癌症发展过程中的相关性尚不清楚。在这里，我们确定了自噬在调节血小板衍生生长因子受体α(PDGFRA)信号和水平中的作用。我们发现，PDGFRA可以通过自噬货物受体p62的活性而成为自噬降解的靶点。结果，短期自噬抑制导致PDGFRA水平升高，但由于受干扰的受体运输，PDGFA介导的信号转导出现意外缺陷。在长时间的自噬抑制过程中，PDGFRA信号缺陷导致其水平降低，这表明了一种适应机制。重要的是，当自噬以依赖于Ptenatus的方式被抑制时，PDGFA驱动的小鼠胶质瘤发生被破坏，从而突出了自噬在肿瘤发生中的特定基因作用。总之，我们的数据提供了一种机制，通过这种机制，细胞需要自噬来驱动肿瘤的形成。
Autophagy is a conserved cellular degradation process. While autophagy-related proteins were shown to influence the signaling and trafficking of some receptor tyrosine kinases, the relevance of this during cancer development is unclear. Here, we identify a role for autophagy in regulating platelet-derived growth factor receptor alpha (PDGFRA) signaling and levels. We find that PDGFRA can be targeted for autophagic degradation through the activity of the autophagy cargo receptor p62. As a result, short-term autophagy inhibition leads to elevated levels of PDGFRA but an unexpected defect in PDGFA-mediated signaling due to perturbed receptor trafficking. Defective PDGFRA signaling led to its reduced levels during prolonged autophagy inhibition, suggesting a mechanism of adaptation. Importantly, PDGFA-driven gliomagenesis in mice was disrupted when autophagy was inhibited in a manner dependent onPtenstatus, thus highlighting a genotype-specific role for autophagy during tumorigenesis. In summary, our data provide a mechanism by which cells require autophagy to drive tumor formation.