Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dev Cell. 2014 Dec 8;31(5):572-85. doi: 10.1016/j.devcel.2014.10.025.
Disassembly of focal adhesions (FAs) allows cell retraction and integrin detachment from the extracellular matrix, processes critical for cell movement. Growth of microtubules (MTs) can promote FA turnover by serving as tracks to deliver proteins essential for FA disassembly. The molecular nature of this FA "disassembly factor," however, remains elusive. By quantitative proteomics, we identified mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) as an FA regulator that associates with MTs. Knockout of MAP4K4 stabilizes FAs and impairs cell migration. By exploring underlying mechanisms, we further show that MAP4K4 associates with ending binding 2 (EB2) and IQ motif and SEC7 domain-containing protein 1 (IQSEC1), a guanine nucleotide exchange factor specific for Arf6, whose activation promotes integrin internalization. Together, our findings provide critical insight into FA disassembly, suggesting that MTs can deliver MAP4K4 toward FAs through EB2, where MAP4K4 can, in turn, activate Arf6 via IQSEC1 and enhance FA dissolution.
焦点黏附（FA）的解体允许细胞回缩，整合素从细胞外基质上脱离，这是细胞运动的关键过程。微管（MTs）的生长可以通过作为输送FA 解体所需蛋白质的轨道来促进 FA 的周转。然而，这种 FA“解体因子”的分子性质仍然难以捉摸。通过定量蛋白质组学，我们发现丝裂原活化蛋白激酶激酶激酶激酶 4（MAP4K4）是一种与 MTs 相关的 FA 调节剂。MAP4K4 的敲除稳定了 FA 并损害了细胞迁移。通过探索潜在的机制，我们进一步表明 MAP4K4 与末端结合蛋白 2（EB2）和 IQ 基序和 SEC7 结构域蛋白 1（IQSEC1）相关，IQSEC1 是一种针对 Arf6 的鸟嘌呤核苷酸交换因子，其激活促进整合素内化。总之，我们的发现为 FA 解体提供了重要的见解，表明 MTs 可以通过 EB2 将 MAP4K4 递送至 FA，MAP4K4 可以通过 IQSEC1 转而激活 Arf6 并增强 FA 溶解。
