Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dev Cell. 2019 May 6;49(3):444-460.e9. doi: 10.1016/j.devcel.2019.04.007.
Actin assembly supplies the structural framework for cell morphology and migration. Beyond structure, this actin framework can also be engaged to drive biochemical signaling programs. Here, we describe how the hyperactivation of Rac1 via the P29S mutation (Rac1) in melanoma hijacks branched actin network assembly to coordinate proliferative cues that facilitate metastasis and drug resistance. Upon growth challenge, Rac1-harboring melanoma cells massively upregulate lamellipodia formation by dendritic actin polymerization. These extended lamellipodia form a signaling microdomain that sequesters and phospho-inactivates the tumor suppressor NF2/Merlin, driving Rac1 cell proliferation in growth suppressive conditions. These biochemically active lamellipodia require cell-substrate attachment but not focal adhesion assembly and drive proliferation independently of the ERK/MAPK pathway. These data suggest a critical link between cell morphology and cell signaling and reconcile the dichotomy of Rac1's regulation of both proliferation and actin assembly by revealing a mutual signaling axis wherein actin assembly drives proliferation in melanoma.
肌动蛋白组装为细胞形态和迁移提供了结构框架。除了结构，这个肌动蛋白框架还可以参与驱动生化信号程序。在这里，我们描述了黑色素瘤中通过 P29S 突变（Rac1）使 Rac1 过度激活如何劫持分支肌动蛋白网络组装，以协调促进转移和耐药性的增殖线索。在生长挑战下，携带 Rac1 的黑色素瘤细胞通过树突状肌动蛋白聚合大量地上调片状伪足形成。这些延伸的片状伪足形成一个信号微域，隔离并使肿瘤抑制因子 NF2/Merlin 磷酸化失活，在生长抑制条件下驱动 Rac1 细胞增殖。这些具有生物化学活性的片状伪足需要细胞-底物附着，但不需要焦点附着组装，并独立于 ERK/MAPK 途径驱动增殖。这些数据表明细胞形态和细胞信号之间存在关键联系，并通过揭示肌动蛋白组装在黑色素瘤中驱动增殖的相互信号轴，调和了 Rac1 对增殖和肌动蛋白组装的调节的二分法。
