title: ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex.
abstract: 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. michelle_mendoza@hms.harvard.edu
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Mendoza
authors.forename: E Emrah
authors.initials: EE
authors.lastname: Er
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Ballif
authors.forename: Hunter L
authors.initials: HL
authors.lastname: Elliott
authors.forename: Gaudenz
authors.initials: G
authors.lastname: Danuser
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011554:Pseudopodia / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*
chemical_list: C513733:ABI1 protein, human; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D051300:Wiskott-Aldrich Syndrome Protein Family; D048049:Extracellular Signal-Regulated MAP Kinases