Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2013 Jul 26;288(30):21784-92. doi: 10.1074/jbc.M113.472704. Epub 2013 Jun 11.
Smad ubiquitin regulatory factors (Smurfs) are HECT-domain ubiquitin E3 ligases that regulate diverse cellular processes, including normal and tumor cell migration. However, the underlying mechanism of the Smurfs' role in cell migration is not fully understood. Here we show that Smurf1 induces ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) at K190. Using the K190R mutant of TRAF4, we demonstrate that Smurf1-induced ubiquitination is required for proper localization of TRAF4 to tight junctions in confluent epithelial cells. We further show that TRAF4 is essential for the migration of both normal mammary epithelial and breast cancer cells. The ability of TRAF4 to promote cell migration is also dependent on Smurf1-mediated ubiquitination, which is associated with Rac1 activation by TRAF4. These results reveal a new regulatory circuit for cell migration, consisting of Smurf1-mediated ubiquitination of TRAF4 and Rac1 activation.
Smad 泛素调节因子（Smurfs）是具有 HECT 结构域的泛素 E3 连接酶，可调节多种细胞过程，包括正常和肿瘤细胞的迁移。然而，Smurfs 在细胞迁移中的作用的潜在机制尚不完全清楚。在这里，我们表明 Smurf1 诱导肿瘤坏死因子受体相关因子 4（TRAF4）在 K190 处的泛素化。使用 TRAF4 的 K190R 突变体，我们证明 Smurf1 诱导的泛素化对于 TRAF4 在细胞紧密连接处的正确定位是必需的。我们进一步表明，TRAF4 对于正常乳腺上皮细胞和乳腺癌细胞的迁移都是必需的。TRAF4 促进细胞迁移的能力也依赖于 Smurf1 介导的泛素化，这与 TRAF4 激活 Rac1 有关。这些结果揭示了一个新的细胞迁移调节回路，由 Smurf1 介导的 TRAF4 泛素化和 Rac1 激活组成。
