Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration.
Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration.
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DOI：
10.1038/s41467-021-25916-6
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发表时间：
2021-09-28
影响因子：
16.6
通讯作者：
Krause M
中科院分区：
文献类型：
--
作者：
Law AL;Jalal S;Pallett T;Mosis F;Guni A;Brayford S;Yolland L;Marcotti S;Levitt JA;Poland SP;Rowe-Sampson M;Jandke A;Köchl R;Pula G;Ameer-Beg SM;Stramer BM;Krause M
细胞迁移对于发育是重要的，其异常调节导致许多疾病。Scar/WAVE复合物是间充质细胞迁移过程中Arp 2/3介导的板状伪足形成所必需的，有几个信号同时激活了它，但迄今为止，还没有发现直接的负调控因子。在这里，我们确定Nance-Horan综合征样蛋白1（NHSL 1）作为疤痕/波复合物的直接结合伴侣，共同定位在突出的板状伪足。这种相互作用由阿比特龙SH 3结构域和NHSL 1中的两个结合位点介导。此外，活性Rac在介导NHSL 1的前缘靶向的两个区域与NHSL 1结合。令人惊讶的是，NHSL 1通过与Scar/WAVE复合物的相互作用抑制细胞迁移。从机制上讲，NHSL 1可以通过阻碍Arp 2/3活性来降低细胞迁移效率，如使用Arp 2/3 FRET-FLIM生物传感器在细胞中测量的，导致板状伪足的F-肌动蛋白密度降低，并因此损害板状伪足突起的稳定性。细胞迁移对于许多生理过程是必不可少的。它的失调会导致癌症转移，并且还不清楚它是如何被严格控制的。我们确定NHSL 1作为肌动蛋白成核Scar/WAVE-Arp 2/3复合物、细胞突起稳定性和细胞迁移的负调节因子。
Cell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. Here we identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions. Cell migration is essential for many physiological processes. Its deregulation causes cancer metastasis and it is not well understood how it is tightly controlled. We identify NHSL1 as a negative regulator of actin nucleating Scar/WAVE-Arp2/3 complexes, cell protrusion stability, and cell migration.