ERK-MAPK Drives Lamellipodia Protrusion by Activating the WAVE2 Regulatory Complex

• Published in: Molecular cell 2011-03, Vol.41 (6), p.661-671
• Main Authors: Mendoza, Michelle C., Er, E. Emrah, Zhang, Wenjuan, Ballif, Bryan A., Elliott, Hunter L., Danuser, Gaudenz, Blenis, John
• Format: Article
• Language: English
• Subjects: actin; Actin-Related Protein 2-3 Complex - genetics; Actin-Related Protein 2-3 Complex - metabolism; Actins - genetics; Actins - metabolism; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; adhesion; cell movement; Cell Movement - physiology; Cells, Cultured; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Epithelial Cells - cytology; Epithelial Cells - physiology; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; mitogen-activated protein kinase; Phosphorylation; polymerization; pseudopodia; Pseudopodia - metabolism; Wiskott-Aldrich Syndrome Protein Family - genetics; Wiskott-Aldrich Syndrome Protein Family - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.02.031

Cell movement begins with a leading edge protrusion, which is stabilized by nascent adhesions and retracted by mature adhesions. The ERK-MAPK (extracellular signal-regulated kinase-mitogen-activated protein kinase) localizes to protrusions and adhesions, but how it regulates motility is not understood. We demonstrate that ERK controls protrusion initiation and protrusion speed. Lamellipodial protrusions are generated via the WRC (WAVE2 regulatory complex), which activates the Arp2/3 actin nucleator for actin assembly. The WRC must be phosphorylated to be activated, but the sites and kinases that regulate its intermolecular changes and membrane recruitment are unknown. We show that ERK colocalizes with the WRC at lamellipodial leading edges and directly phosphorylates two WRC components: WAVE2 and Abi1. The phosphorylations are required for functional WRC interaction with Arp2/3 and actin during cell protrusion. Thus, ERK coordinates adhesion disassembly with WRC activation and actin polymerization to promote productive leading edge advancement during cell migration. [Display omitted] ► ERK activity is required for protrusion and migration speed ► ERK colocalizes with the WRC at the leading edge ► ERK directly phosphorylates WAVE2 and Abi1 ► WRC phosphorylation promotes functional WRC interaction with Arp2/3 and actin