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: 14.02). 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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    • "Regulation of actin nucleation by β-arrestins has not been directly shown, although several proteins involved in actin nucleation have been identified as β-arrestin-dependent ERK1/2 targets. Arp2/3 complex components and Wiskott–Adrich syndrome protein (WASp) family proteins have been identified in a proteomics screen as potential β-arrestin-interacting proteins (Xiao et al. 2007) and phosphorylation targets of MAPK (Christensen et al. 2010) and activation of WASp family proteins is enhanced by ERK1/2 phosphorylation (Mendoza Michelle et al. 2011). The Arp2/3 complex, along with formins and p150spir, is the primary nucleation factor in mammalian cells (Campellone and Welch 2010; Firat-Karalar and Welch 2011). "
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    Handbook of experimental pharmacology 01/2014; 219:341-59. DOI:10.1007/978-3-642-41199-1_17
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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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    ABSTRACT: SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein and as an effector of MRAS. Here we show that SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.
    Molecular cell 11/2013; 12(12 Supplement). DOI:10.1016/j.molcel.2013.10.004 · 14.02 Impact Factor
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    • "The Ras-ERK1/2 MAP kinase pathway plays a critical role in numerous cellular processes, including proliferation, differentiation, survival, and motility [20]. Growth factors activate ERK-MAPK by signaling through their cognate receptors at the cell surface to the small GTPase Ras. "
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