Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes

Innocenti, Metello; Gerboth, Silke; Rottner, Klemens; Lai, Frank P. L.; Hertzog, Maud; Stradal, Theresia E. B.; Frittoli, Emanuela; Didry, Dominique; Polo, Simona; Disanza, Andrea; Benesch, Stefanie; Fiore, Pier Paolo Di; Carlier, Marie‐France; Scita, Giorgio

doi:10.1038/ncb1304

Cited by 203 publications

(217 citation statements)

References 43 publications

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“…The levels of WAVE2 complex components WAVE2, Sra-1/PIR121, and Nap1 were significantly lower in cells lacking Abi1. These data are consistent with previous siRNA knockdown experiments showing that upon down- regulation of individual subunits, the remaining components of the WAVE2 complex are coordinately decreased (11,(37)(38)(39). Our results demonstrate that lack of Abi1 caused significant instability of the WAVE2 complex, thus confirming the critical role of Abi1 in the complex function.…”

Section: Discussionsupporting

confidence: 82%

“…Rho GTPases are modulated by complexes of Abi1 with Eps8-Sos1 (9, 10) and downstream actin polymerization e.g. by N-WASP (11) and WAVE complex (12)(13)(14). The ubiquitous WAVE complex, comprising the direct Rac interactor Sra-1/PIR121, its binding partner Nap1, plus Abi1, HSPC300/Brick1, and WAVE2, is considered to be the essential functional output module linking Rac1 activation to actin polymerization that drives lamellipodia protrusion at the plasma membrane (13,14).…”

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confidence: 99%

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Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Dubielecka

Ladwein

Xiong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Abl interactor 1 (Abi1) plays a critical function in actin cytoskeleton dynamics through participation in the WAVE2 complex. To gain a better understanding of the specific role of Abi1, we generated a conditional Abi1-KO mouse model and MEFs lacking Abi1 expression. Abi1-KO cells displayed defective regulation of the actin cytoskeleton, and this dysregulation was ascribed to altered activity of the WAVE2 complex. Changes in motility of Abi1-KO cells were manifested by a decreased migration rate and distance but increased directional persistence. Although these phenotypes did not correlate with peripheral ruffling, which was unaffected, Abi1-KO cells exhibited decreased dorsal ruffling. Western blotting analysis of Abi1-KO cell lysates indicated reduced levels of the WAVE complex components WAVE1 and WAVE2, Nap1, and Sra-1/PIR121. Although relative Abi2 levels were more than doubled in Abi1-KO cells, the absolute Abi2 expression in these cells amounted only to a fifth of Abi1 levels in the control cell line. This finding suggests that the presence of Abi1 is critical for the integrity and stability of WAVE complex and that Abi2 levels are not sufficiently increased to compensate fully for the loss of Abi1 in KO cells and to restore the integrity and function of the WAVE complex. The essential function of Abi1 in WAVE complexes and their regulation might explain the observed embryonic lethality of Abi1-deficient embryos, which survived until approximately embryonic day 11.5 and displayed malformations in the developing heart and brain. Cells lacking Abi1 and the conditional Abi1-KO mouse will serve as critical models for defining Abi1 function.cell motility | lamellipodium | Rac | Arp2/3-complex | Hssh3bp1

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Dubielecka

Ladwein

Xiong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Consistent with this finding, is the fact that the de novo Arp2/3-dependent actin filament elongation, mediated by the WAVE family of proteins, is essential for the formation of dorsal membrane extensions needed to engulf fluids Innocenti et al, 2005). This pathway is under the control of the RhoGTPase, RAC, which mediates actin remodeling at the plasma membrane (PM) by controlling WASP family VE rprolin-homologous proteins (WAVEs) (Stradal et al, 2004).…”

Section: Introductionmentioning

confidence: 55%

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Frittoli

Palamidessi

Pizzigoni

et al. 2008

MBoC

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The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primatespecific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor-mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3:GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process. INTRODUCTIONGene duplication, exon shuffling, and retrotransposition events played crucial roles during vertebrate evolution (Long, 2001;McLysaght et al., 2002;Brosius, 2003). About 5% of the human genome is composed of duplicated segments that emerged during the past 35 million years of primate evolution, resulting in the generation of novel protein functions (Courseaux and Nahon, 2001;Taylor and Raes, 2004).One of the cellular processes, whose regulation has became more and more complex and tightly regulated during evolution is endocytosis. Endocytosis serves to maintain cellular and organismal homeostasis by mediating the uptake of fluids, solutes, and signaling molecules and their receptors. Multiple mechanisms of endocytosis operate within a single cell (Conner and Schmid, 2003). Among them, two major categories are phagocytosis and pinocytosis, which mediate the uptake of particles or of fluid, respectively (Conner and Schmid, 2003).Pinocytosis encompasses a variety of different membraneentry routes and is invariably characterized by the relatively small size (50 -150 nm) of the internalized particles. Large volumes of fluid are, instead, engulfed by extension, folding, and closure of plasma membranes (PM) through a process termed macropinocytosis (Swanson and Watts, 1995). Macropinocytosis displays many similarities to phagocytosis; the biochemical and cellular components of these endocytic mechanisms have been best characterized in hematopoietic cells, in processes such as phagocytosis by macrophages in response to Fc receptor stimulation, or ma...

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“…Abi proteins localize to sites of actin polymerization at cellcell contacts in epithelial adherens junctions (8,9) and immune synapses (15). Abi proteins also localize to the leading edge of lamellipodia, and this localization correlates with positive regulation of directional migration (12,16,17). Regulation of protrusive activity by Abi proteins has been linked to the formation of protein complexes with the WASP/WAVE family of nucleation-promoting factors (18), leading to activation of the Arp2/3 complex (19).…”

mentioning

confidence: 99%

“…Subsequent in vitro studies have implicated Abi proteins in the regulation of cell motility, intercellular adhesion, endocytosis, cytokinesis, Golgi architecture, and transport carrier biogenesis, through their ability to interact with distinct protein complexes involved in the regulation of actin nucleation (7)(8)(9)(10)(11)(12)(13)(14). Abi proteins localize to sites of actin polymerization at cellcell contacts in epithelial adherens junctions (8,9) and immune synapses (15).…”

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confidence: 99%

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

Ring

Ginsberg

Haling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization through interactions with multiple protein complexes. However, the in vivo role of Abi1 remains to be defined. The α4 integrin adhesion receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 exhibits unique properties in that it predominantly accumulates at the leading edge of migrating cells; however, the pathways that link the actin-regulatory machinery to α4 at the leading edge have remained elusive. We generated Abi1 KO mice and found that loss of Abi1 phenocopies KO of α4. Mice lacking Abi1 or α4 exhibit midgestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 colocalizes with phosphorylated α4 at the leading edge of spreading cells. Moreover, Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by WT Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal a direct link between the α4 integrin and actin polymerization and uncover a role for Abi1 in the regulation of morphogenesis in vivo. The Abi1–α4 interaction establishes a mechanistic paradigm for signaling between adhesion events and enhanced actin polymerization at the earliest stages of protrusion.

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Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes

Cited by 203 publications

References 43 publications

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

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