Neuropilin-2 Regulates Endosome Maturation and EGFR Trafficking to Support Cancer Cell Pathobiology.
Neuropilin-2 Regulates Endosome Maturation and EGFR Trafficking to Support Cancer Cell Pathobiology.
复制标题
DOI：
10.1158/0008-5472.can-15-1488
复制
发表时间：
2016-01-15
期刊：
影响因子：
11.2
通讯作者：
Datta K
中科院分区：
文献类型：
--
作者：
Dutta S;Roy S;Polavaram NS;Stanton MJ;Zhang H;Bhola T;Hönscheid P;Donohue TM Jr;Band H;Batra SK;Muders MH;Datta K
神经粘连蛋白-2(NRP2)是一种非酪氨酸激酶受体，常在多种恶性肿瘤中过度表达，参与促进多种促癌行为，如对转移性癌细胞的治疗耐药。在这里，我们报告了NRP2作为内吞作用的一种新的功能，它在癌细胞中得到增强，并经常与转移潜能和耐药性的增加有关。我们发现，人前列腺癌和胰腺癌细胞中NRP2的缺失导致了EEA1/Rab5阳性的早期内小体的积累，同时伴随着Rab7阳性的晚期内小体的减少，这表明内小体的早期和晚期成熟被推迟。NRP2的缺失还损害了细胞表面表皮生长因子受体(EGFR)的胞内转运，阻止了功能活跃的EGFR进入内吞囊泡，从而导致ERK异常激活和细胞死亡。机制研究表明，WD-Repeat和FYVE结构域蛋白1(WDFY1)在NRP2下游发挥作用，促进内体成熟，从而影响EGFR的内体转运和负责内化货物降解的自溶酶体的形成。总体而言，我们的结果表明，NRP2/WDFY1轴是维持癌细胞内吞活性所必需的，这支持了癌细胞的致癌活性并赋予了耐药性。因此，治疗靶向内吞作用可能是一种有吸引力的策略，可以选择性地靶向多种恶性肿瘤的癌细胞。
Neuropilin-2 (NRP2) is a non-tyrosine kinase receptor frequently overexpressed in various malignancies where it has been implicated in promoting many protumorigenic behaviors, such as imparting therapeutic resistance to metastatic cancer cells. Here, we report a novel function of NRP2 as a regulator of endocytosis, which is enhanced in cancer cells and is often associated with increased metastatic potential and drug resistance. We found that NRP2 depletion in human prostate and pancreatic cancer cells resulted in the accumulation of EEA1/Rab5-positive early endosomes concomitant with a decrease in Rab7-positive late endosomes, suggesting a delay in early-to-late endosome maturation. NRP2 depletion also impaired the endocytic transport of cell surface epidermal growth factor receptor (EGFR), arresting functionally active EGFR in endocytic vesicles that consequently led to aberrant ERK activation and cell death. Mechanistic investigations revealed that WD-repeat and FYVE-domain-containing protein 1 (WDFY1) functioned downstream of NRP2 to promote endosome maturation, thereby influencing the endosomal trafficking of EGFR and the formation of autolysosomes responsible for the degradation of internalized cargo. Overall, our results indicate that the NRP2/WDFY1 axis is required for maintaining endocytic activity in cancer cells, which supports their oncogenic activities and confers drug resistance. Therefore, therapeutically targeting endocytosis may represent an attractive strategy to selectively target cancer cells in multiple malignancies.