The scaffolding protein Flot2 regulates cytoneme-based transport of Wnt3 in gastric cancer
The scaffolding protein Flot2 regulates cytoneme-based transport of Wnt3 in gastric cancer
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DOI：
10.1101/2022.01.07.475396
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
D. Routledge;Sally Rogers;H. Ashktorab;T. Phesse;S. Scholpp
中科院分区：
文献类型：
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作者：
D. Routledge;Sally Rogers;H. Ashktorab;T. Phesse;S. Scholpp
Wnt/β-Catenin信号通路在发育和许多疾病过程中调节多种细胞过程，包括细胞的增殖、迁移和分化。尽管Wnt蛋白具有疏水性，但它们在很长的距离内发挥着诱导旁分泌信号的功能。最近的研究已经确定了几个与Wnt分泌有关的因素，然而，我们对Wnt配体如何在细胞之间转运以与其同源受体相互作用的理解仍存在争议。在这里，我们证明了胃癌细胞利用细胞素转运WNT3细胞间促进增殖。此外，我们发现在胃癌中经常过度表达的膜结合支架蛋白Flotillin-2(Flot2)是这些细胞素的调节因子。Flot2与WnT共受体和细胞素启动子Ror2一起决定了胃癌中WNT3细胞素的数量和长度。最后，我们发现在斑马鱼胚胎发育过程中，Flot2对Wnt8a细胞线是必需的，这表明Flot2介导的Wnt在细胞线上的运输在发育和疾病中是一个保守的机制。
The Wnt/β-catenin signalling pathway regulates multiple cellular processes during development and many diseases, including cell proliferation, migration, and differentiation. Despite their hydrophobic nature, Wnt proteins exert their function over long distances to induce paracrine signalling. Recent studies have identified several factors involved in Wnt secretion, however, our understanding of how Wnt ligands are transported between cells to interact with their cognate receptors is still debated. Here, we demonstrate that gastric cancer cells utilise cytonemes to transport Wnt3 intercellularly to promote proliferation. Furthermore, we identify the membrane-bound scaffolding protein Flotillin-2 (Flot2), frequently overexpressed in gastric cancer, as a regulator of these cytonemes. Together with the Wnt co-receptor and cytoneme initiator Ror2, Flot2 determines the number and length of Wnt3 cytonemes in gastric cancer. Finally, we show that Flot2 is necessary for Wnt8a cytonemes during zebrafish embryogenesis, suggesting a conserved mechanism for Flot2-mediated Wnt transport on cytonemes in development and disease.