Vaughan Lynsey, Tan Chong-Teik, Chapman Anna, Nonaka Daisuke, Mack Natalie A, Smith Duncan, Booton Richard, Hurlstone Adam F L, Malliri Angeliki
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Cell Rep. 2015 Jan 6;10(1):88-102. doi: 10.1016/j.celrep.2014.12.012. Epub 2014 Dec 24.
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.
E3泛素连接酶HUWE1在癌症中失调，与肿瘤形成有关。在此，我们发现HUWE1通过降解RAC激活剂TIAM1在细胞迁移和侵袭中发挥作用，这意味着它在恶性进展中具有额外功能。在响应HGF的MDCKII细胞中，HUWE1主要在细胞间黏附处催化TIAM1的泛素化和降解，促进连接解离、迁移和侵袭。敲低HUWE1或使TIAM1泛素化位点突变可阻止TIAM1降解，拮抗散射和侵袭。此外，同时敲低TIAM1可恢复HUWE1敲低细胞的迁移和侵袭能力。重要的是，我们表明HUWE1通过调节TIAM1稳定性刺激人肺癌细胞侵袭。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在调节上皮细胞间黏附中的关键作用，并提供了额外证据表明泛素化有助于RAC的时空控制。
