HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion.
HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion.
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DOI：
10.1016/j.celrep.2014.12.012
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发表时间：
2015-01-06
期刊：
影响因子：
8.8
通讯作者：
Malliri A
中科院分区：
文献类型：
--
作者：
Vaughan L;Tan CT;Chapman A;Nonaka D;Mack NA;Smith D;Booton R;Hurlstone AF;Malliri A
E3泛素连接酶HUWE1在癌中失调控，与肿瘤形成有关。在这里，我们发现HUWE1通过降解RAC激活子TIAM1在细胞迁移和侵袭中的作用，这意味着在恶性进展中有额外的功能。在响应HGF的MDCKII细胞中，HUWE1主要在细胞-细胞粘附中催化TIAM1泛素化和降解，促进连接拆卸、迁移和侵袭。耗尽HUWE1或突变TIAM1泛素化位点可阻止TIAM1降解、拮抗散射和入侵。此外，TIAM1的同时缺失可以恢复huwe1缺失细胞的迁移和侵袭。值得注意的是，我们发现HUWE1通过调节TIAM1的稳定性来刺激人肺癌细胞的侵袭。最后，我们证明HUWE1和TIAM1蛋白水平在人肺癌中呈负相关。因此，我们阐明了HUWE1在调节上皮细胞-细胞粘附中的关键作用，并提供了泛素化有助于RAC时空控制的额外证据。HGF诱导的细胞-细胞粘附拆卸、迁移和侵袭需要HUWE1，在细胞-细胞粘附过程中，HUWE1泛素化并降解TIAM1，以响应HGF。TIAM1是HUWE1调控细胞-细胞粘附、运动和侵袭的关键靶点，在肺癌中，HUWE1和TIAM1表达水平呈负相关，上皮肿瘤细胞的恶性转化尚不完全清楚。在这里，Vaughan等人证明了E3连接酶HUWE1在HGF刺激后降解RAC激活剂TIAM1，促进包括肺癌细胞在内的上皮细胞的细胞连接拆卸、运动和侵袭。这表明HUWE1在肺癌传播中起着关键作用。
The E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC. HGF-induced cell-cell adhesion disassembly, migration, and invasion require HUWE1 HUWE1 ubiquitylates and degrades TIAM1 at cell-cell adhesions in response to HGF TIAM1 is the key HUWE1 target regulating cell-cell adhesion, motility, and invasion HUWE1 and TIAM1 expression levels are inversely correlated in lung cancer Malignant conversion of epithelial tumor cells is incompletely understood. Here, Vaughan et al. demonstrate that the E3 ligase HUWE1 degrades the RAC activator TIAM1 following HGF stimulation, promoting cell junction disassembly, motility, and invasion in epithelial cells including lung cancer cells. This indicates a critical role for HUWE1 in lung cancer dissemination.