Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
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DOI：
10.1038/s41467-023-39640-w
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发表时间：
2023-07-19
影响因子：
16.6
通讯作者：
Chapkin, Robert S.
中科院分区：
文献类型：
--
作者：
Erazo-Oliveras, Alfredo;Munoz-Vega, Monica;Mlih, Mohamed;Thiriveedi, Venkataramana;Salinas, Michael L.;Rivera-Rodriguez, Jaileen M.;Kim, Eunjoo;Wright, Rachel C.;Wang, Xiaoli;Landrock, Kerstin K.;Goldsby, Jennifer S.;Mullens, Destiny A.;Roper, Jatin;Karpac, Jason;Chapkin, Robert S.
尽管Wnt通路在结肠癌发生中的作用已经在之前描述过，但最近已经证明Wnt信号传导起源于质膜上的高度动态纳米组装。然而，关于致癌APC在重塑Wnt纳米结构域中的作用知之甚少。这是值得注意的，因为致癌APC不自主地起作用，并且需要激活APC上游的Wnt效应物来驱动异常的Wnt信号传导。在这里，我们证明了致癌APC在增加质膜游离胆固醇和硬度，从而调节Wnt信号枢纽的作用。这导致结肠中Wnt信号的过度激活。最后，使用果蝇甾醇营养缺陷型模型，我们证明了独特的能力，外源性游离胆固醇破坏质膜稳态和驱动Wnt信号在野生型APC背景。总的来说，这些发现提供了致癌APC、质膜稳态丧失和CRC发展之间的联系。动态蛋白脂质纳米组装体在质膜的结肠细胞作为Wnt信号枢纽。在这里，作者发现突变型APC在结直肠癌中质膜固醇稳态失调中的作用。
Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development. Dynamic proteolipid nanoassemblies at the plasma membrane of colonocytes serve as Wnt signaling hubs. Here, the authors find a role for mutant APC in colorectal cancer in the dysregulation of plasma membrane sterol homeostasis.
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影响因子：
6.5
作者：
Fuentes NR;Mlih M;Wang X;Webster G;Cortes-Acosta S;Salinas ML;Corbin IR;Karpac J;Chapkin RS
通讯作者：
Chapkin RS
各种人类截短的腺瘤性息肉病大肠杆菌同工型在控制β-蛋白 - - - - - - 钙蛋白活性和细胞增殖中）的共同作用。
影响因子：
3.7
作者：
Chandra SH;Wacker I;Appelt UK;Behrens J;Schneikert J
通讯作者：
Schneikert J
影响因子：
4.4
作者：
Halvey, Patrick J.;Zhang, Bing;Coffey, Robert J.;Liebler, Daniel C.;Slebos, Robbert J. C.
通讯作者：
Slebos, Robbert J. C.
影响因子：
4.3
作者：
Apidianakis Y;Rahme LG
通讯作者：
Rahme LG
影响因子：
4.6
作者：
Carvalho, Maria;Schwudke, Dominik;Eaton, Suzanne
通讯作者：
Eaton, Suzanne