TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling.
TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling.
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DOI：
10.1038/s41556-018-0219-8
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发表时间：
2018-12
影响因子：
21.3
通讯作者：
Park JI
中科院分区：
文献类型：
--
作者：
Jung YS;Jun S;Kim MJ;Lee SH;Suh HN;Lien EM;Jung HY;Lee S;Zhang J;Yang JI;Ji H;Wu JY;Wang W;Miller RK;Chen J;McCrea PD;Kopetz S;Park JI
囊泡酸化和运输与各种细胞过程有关。然而，它们与癌症的病理相关性仍然难以捉摸。我们确定跨膜蛋白9（TMEM 9）作为一个囊泡酸化调节剂。TMEM 9在结直肠癌（CRC）中高度上调。蛋白质组学和生物化学分析表明，TMEM 9结合并促进v-ATP酶（一种液泡质子泵）的组装，导致囊泡酸化和运输增强。TMEM 9-v-ATP酶通过APC的溶酶体降解过度激活Wnt/β-连环蛋白信号传导。此外，由β-连环蛋白反式激活的TMEM 9在CRC中充当Wnt信号传导的正反馈调节剂。TMEM 9的基因消融在体外、离体和体内小鼠模型中抑制CRC细胞增殖。此外，施用v-ATP酶抑制剂抑制APC小鼠模型和人类患者来源的异种移植物的肠肿瘤发生。我们的研究结果揭示了TMEM 9控制的囊泡酸化在通过APC降解过度激活Wnt/β-连环蛋白信号传导中的意想不到的作用，并提出TMEM 9-v-ATPase的阻断作为CRC治疗的可行选择。
Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer (CRC). Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of v-ATPase, a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signaling via lysosomal degradation of APC. Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signaling in CRC. Genetic ablation of TMEM9 inhibits CRC cell proliferation in vitro, ex vivo, and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/β-catenin signaling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for CRC treatment.
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影响因子：
--
作者：
Najdi R;Holcombe RF;Waterman ML
通讯作者：
Waterman ML
影响因子：
64.8
作者：
Park, Jae-Il;Venteicher, Andrew S.;Hong, Ji Yeon;Choi, Jinkuk;Jun, Sohee;Shkreli, Marina;Chang, Woody;Meng, Zhaojing;Cheung, Peggie;Ji, Hong;McLaughlin, Margaret;Veenstra, Timothy D.;Nusse, Roel;McCrea, Pierre D.;Artandi, Steven E.
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Artandi, Steven E.
影响因子：
50.3
作者：
O'Brien, Catherine A.;Kreso, Antonija;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
56.9
作者：
Bilic, Josipa;Huang, Ya-Lin;Niehrs, Christof
通讯作者：
Niehrs, Christof
影响因子：
7.2
作者：
Cadigan, Ken M.;Waterman, Marian L.
通讯作者：
Waterman, Marian L.