ERK3/MAPK6 dictates CDC42/RAC1 activity and ARP2/3-dependent actin polymerization
Mechanisms that control cell migration and morphology are actively being studied in many different disease settings, and while the actin cytoskeleton plays an essential role, the mechanisms that regulate actin are still under intense investigation. Recently, Bogucka-Janczi et al. identified ERK3 as a novel regulator of the actin cytoskeleton in the setting of cancer cell migration. The group performed preliminary studies showing co-localization of ERK3 with F-actin-rich protrusions in human mammary epithelial cells. Knockdown of ERK3 in cancer cells reduced both random motility as well as EGF-induced chemotaxis. To further define the regulatory signaling mechanisms, the group investigated the impact of ERK3 on small GTPases like Rac1 and Cdc42. Interestingly, they found that ERK3 directly binds to both of these small GTPases at low nM affinities and can function as a GEF to enhance Cdc42 activation. They also observed that ERK3 depletion via CRISPR or shRNA led to a decrease in F-actin/G-Actin ratios in primary epithelial and cancer cell lines, which led them to investigate interactions with actin-binding proteins. They showed that ERK3 kinase directly interacted with ARP3, phosphorylated ARP3 at S418, and determined that ERK3 was sufficient to promote ARP2/3-dependent actin polymerization. Collectively these data show that ERK3 controls F-actin through regulation of ARP2/3 and Cdc42 dependent mechanisms; several Cytoskeleton Inc tools such as RhoGEF Exchange Assay (Cat. # BK100), G-Actin/F-Actin In Vivo Assay Biochem Kit (Cat. # BK037), and the Actin Polymerization Biochem Kit (Cat. # BK003) were essential tools in this investigation.
Above: Schematic showing the mechanisms by which ERK3 interacts with multiple actin regulatory proteins to control actin polymerization and ultimately cell motility.
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