EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis
EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis
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DOI：
10.1016/j.devcel.2019.05.043
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发表时间：
2019-08-05
影响因子：
11.8
通讯作者：
Commissol, Cosimo
中科院分区：
文献类型：
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作者：
Lee, Szu-Wei;Zhang, Yijuan;Commissol, Cosimo
巨胞饮作用已成为支持肿瘤细胞健康的重要营养物清除途径。通过内化细胞外蛋白并靶向其进行溶酶体降解，这种内吞途径充当氨基酸供应途径，允许肿瘤细胞在肿瘤微环境营养不良的条件下生长和存活。在这里，我们提供的证据表明，胰腺导管腺癌（PDAC）肿瘤的一个子集能够整合背景代谢输入来调节巨胞饮作用，根据营养物质的可用性来调高或调低该摄取途径。我们发现氨基酸的区域性消耗与巨胞饮水平的增加同时发生，而谷氨酰胺的稀缺独特地驱动了这一过程。从机制上讲，这种巨胞饮作用的刺激取决于营养应激诱导的表皮生长因子受体信号传导增强，通过 Pak 的激活，控制这些细胞中巨胞饮作用的程度。这些结果提供了对营养线索如何控制 PDAC 肿瘤中蛋白质清除的机制理解。
Macropinocytosis has emerged as an important nutrient-scavenging pathway that supports tumor cell fitness. By internalizing extracellular protein and targeting it for lysosomal degradation, this endocytic pathway functions as an amino acid supply route, permitting tumor cell growth and survival despite the nutrient-poor conditions of the tumor microenvironment. Here, we provide evidence that a subset of pancreatic ductal adenocarcinoma (PDAC) tumors are wired to integrate contextual metabolic inputs to regulate macropinocytosis, dialing up or down this uptake pathway depending on nutrient availability. We find that regional depletion of amino acids coincides with increased levels of macropinocytosis and that the scarcity of glutamine uniquely drives this process. Mechanistically, this stimulation of macropinocytosis depends on the nutrient stress-induced potentiation of epidermal growth factor receptor signaling that, through the activation of Pak, controls the extent of macropinocytosis in these cells. These results provide a mechanistic understanding of how nutritional cues can control protein scavenging in PDAC tumors.