The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation
The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation
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DOI：
10.1038/onc.2012.189
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发表时间：
2013-03-28
期刊：
影响因子：
8
通讯作者：
Malliri, A.
中科院分区：
文献类型：
--
作者：
Castillo-Lluva, S.;Tan, C-T;Malliri, A.
小的GTdR Rac 1是细胞运动的关键调节因子。多种机制调节Rac 1活性，包括其泛素化和随后的降解。在这里，我们确定肿瘤抑制因子HACE 1（HECT域和锚蛋白重复包含E3泛素蛋白连接酶1）作为E3泛素连接酶负责Rac 1降解激活后的迁移刺激。我们发现，肝细胞生长因子（HGF）信号，一个Rac激活剂和细胞迁移的有力刺激，增强了HACE 1和Rac 1的相互作用。此外，HACE 1催化Rac 1在被HGF激活后在赖氨酸147处的多泛素化，导致其蛋白酶体降解。这种负反馈机制可能会限制细胞运动。与此相一致，HACE 1消耗伴随着总Rac 1水平的增加和Rac 1在膜皱褶中的积累。此外，HACE 1-耗竭增强细胞迁移独立的生长因子刺激，这可能有意义的恶性转化。非泛素化Rac 1比野生型Rac 1在更大程度上挽救了Rac 1缺失细胞的迁移缺陷。这些发现通过其降解活性Rac 1的能力将HACE 1鉴定为细胞迁移的拮抗剂。Oncogene（2013）32，1735-1742; doi：10.1038/onc.2012.189; 2012年5月21日在线发表
The small GTPase Rac1 is a key regulator of cell motility. Multiple mechanisms regulate Rac1 activity including its ubiquitylation and subsequent degradation. Here, we identify the tumour suppressor HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) as an E3 ubiquitin ligase responsible for Rac1 degradation following activation by a migration stimulus. We show that HACE1 and Rac1 interaction is enhanced by hepatocyte growth factor (HGF) signalling, a Rac activator and potent stimulus of cell migration. Furthermore, HACE1 catalyses the poly-ubiquitylation of Rac1 at lysine 147 following its activation by HGF, resulting in its proteasomal degradation. This negative feedback mechanism likely restricts cell motility. Consistent with this, HACE1 depletion is accompanied by increased total Rac1 levels and accumulation of Rac1 in membrane ruffles. Moreover, HACE1-depletion enhances cell migration independently of growth factor stimulation, which may have significance for malignant conversion. A non-ubiquitylatable Rac1 rescues the migration defect of Rac1-null cells to a greater extent than wild-type Rac1. These findings identify HACE1 as an antagonist of cell migration through its ability to degrade active Rac1. Oncogene (2013) 32, 1735-1742; doi:10.1038/onc.2012.189; published online 21 May 2012