Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Departments of Biology and Physics, Wilkes University, Wilkes Barre, United States.
Elife. 2023 Apr 14;12:e85167. doi: 10.7554/eLife.85167.
The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding-proteins and nucleation-promoting factors to perform fundamental cellular functions. We have previously shown that ERK3, an atypical MAPK, controls IL-8 production and chemotaxis (Bogueka et al., 2020). Here, we show in human cells that ERK3 directly acts as a guanine nucleotide exchange factor for CDC42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent RAC1 and CDC42 activation, maintenance of F-actin content, filopodia formation, and epithelial cell migration. Further, ERK3 protein bound directly to the purified ARP2/3 complex and augmented polymerization of actin in vitro. ERK3 kinase activity was required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions.
细胞骨架肌动蛋白被 RhoGTPases、肌动蛋白结合蛋白和核形成促进因子严密调控，以执行基本的细胞功能。我们之前已经表明，ERK3（一种非典型的 MAPK）控制着 IL-8 的产生和趋化作用（Bogueka 等人，2020 年）。在这里，我们在人类细胞中表明，ERK3 直接作为 CDC42 的鸟嘌呤核苷酸交换因子，并磷酸化 ARP2/3 复合物的 ARP3 亚基的 S418，分别促进丝状伪足形成和肌动蛋白聚合。一致地，ERK3 的耗竭阻止了基础和 EGF 依赖性 RAC1 和 CDC42 的激活、F-肌动蛋白含量的维持、丝状伪足的形成和上皮细胞的迁移。此外，ERK3 蛋白直接与纯化的 ARP2/3 复合物结合，并增强体外肌动蛋白的聚合。ERK3 激酶活性对于哺乳动物细胞中富含肌动蛋白的突起的形成是必需的。这些发现揭示了细胞用来控制肌动蛋白依赖性细胞功能的一种基本独特途径。
