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CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation
The Journal of Cell Biology Pub Date : 2021-06-24 , DOI: 10.1083/jcb.202012114
Anh Hoang Le 1, 2 , Tamas Yelland 1 , Nikki R Paul 1 , Loic Fort 1, 3 , Savvas Nikolaou 1, 2 , Shehab Ismail 1 , Laura M Machesky 1, 2
Affiliation  

The Scar/WAVE complex drives actin nucleation during cell migration. Interestingly, the same complex is important in forming membrane ruffles during macropinocytosis, a process mediating nutrient uptake and membrane receptor trafficking. Mammalian CYRI-B is a recently described negative regulator of the Scar/WAVE complex by RAC1 sequestration, but its other paralogue, CYRI-A, has not been characterized. Here, we implicate CYRI-A as a key regulator of macropinosome formation and integrin internalization. We find that CYRI-A is transiently recruited to nascent macropinosomes, dependent on PI3K and RAC1 activity. CYRI-A recruitment precedes RAB5A recruitment but follows sharply after RAC1 and actin signaling, consistent with it being a local inhibitor of actin polymerization. Depletion of both CYRI-A and -B results in enhanced surface expression of the α5β1 integrin via reduced internalization. CYRI depletion enhanced migration, invasion, and anchorage-independent growth in 3D. Thus, CYRI-A is a dynamic regulator of macropinocytosis, functioning together with CYRI-B to regulate integrin trafficking.

中文翻译:

CYRI-A 通过巨胞质体形成和整合素摄取调节限制侵入性迁移

Scar/WAVE 复合物在细胞迁移过程中驱动肌动蛋白成核。有趣的是,相同的复合物在巨胞饮作用(介导营养吸收和膜受体运输的过程)过程中形成膜皱褶方面也很重要。哺乳动物 CYRI-B 是最近描述的通过 RAC1 隔离作用对 Scar/WAVE 复合物负调节的物质,但其其他旁系同源物 CYRI-A 尚未得到表征。在这里,我们认为 CYRI-A 是巨胞质体形成和整合素内化的关键调节因子。我们发现 CYRI-A 短暂地被招募到新生的巨脂质体中,这取决于 PI3K 和 RAC1 的活性。CYRI-A 招募先于 RAB5A 招募,但紧随 RAC1 和肌动蛋白信号传导之后,这与其作为肌动蛋白聚合的局部抑制剂一致。CYRI-A 和 -B 的消耗通过减少内化导致 α5β1 整合素的表面表达增强。CYRI 消耗增强了 3D 中的迁移、侵袭和不依赖锚定的生长。因此,CYRI-A 是巨胞饮作用的动态调节因子,与 CYRI-B 一起发挥作用来调节整合素运输。
更新日期:2021-06-24
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