ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Molecular cell (Impact Factor: 14.46). 03/2011; 41(6):661-71. DOI: 10.1016/j.molcel.2011.02.031
Source: PubMed

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.

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Available from: Michelle C Mendoza, Jul 30, 2015
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    • "The SHOC-SCRIB complex may thus be involved in the regulation of the frequency and amplitude of ERK activity pulses (Albeck et al., 2013; Kholodenko et al., 2010). Spatiotemporal dynamics of ERK activity can have different signaling and biological outputs within the same cell (Kholodenko et al., 2010), and MRAS and SHOC2 may play a preferential role in coordinating the ERK pathway with polarized migration, for example by modulating ERK activity at the leading edge, where ERK can stimulate lamellipodia protrusion by phosphorylating the WAVE regulatory complex (Mendoza et al., 2011). Through SHOC2, MRAS is expected to recruit SCRIB and its associated interactome to sites of activation and thereby coordinate ERK activity with other SCRIB-regulated pathways (Figure S7). "
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