A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans

Croce, Assunta; Cassata, Giuseppe; Disanza, Andrea; Gagliani, Maria Cristina; Tacchetti, Carlo; Malabarba, Maria Grazia; Carlier, Marie‐France; Scita, Giorgio; Baumeister, Ralf; Fiore, Pier Paolo Di

doi:10.1038/ncb1198

Cited by 112 publications

(126 citation statements)

References 20 publications

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“…We found that Eps8 was not essential for dorsal filopodia formation but is involved in modulating their size. This is consistent with the actin-capping role of Eps8 (Croce et al, 2004), where Eps8 prevents the actin filament elongation. In contrast, WAVE2 KD dramatically reduced the number of dorsal membrane ruffles formed and their length.…”

Section: Discussionsupporting

confidence: 75%

The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

Sudhaharan

Sem

Liew

et al. 2016

Journal of Cell Science

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Rif induces dorsal filopodia but the signaling pathway responsible for this has not been identified. We show here that Rif interacts with the I-BAR family protein IRTKS (also known as BAIAP2L1) through its I-BAR domain. Rif also interacts with Pinkbar (also known as BAIAP2L2) in N1E-115 mouse neuroblastoma cells. IRTKS and Rif induce dorsal membrane ruffles and filopodia. Dominant-negative Rif inhibits the formation of IRTKS-induced morphological structures, and Rif activity is blocked in IRTKS-knockout (KO) cells. To further define the Rif-IRTKS signaling pathway, we identify Eps8 and WAVE2 (also known as WASF2) as IRTKS interactors. We find that Eps8 regulates the size and number of dorsal filopodia and membrane ruffles downstream of Rif-IRTKS signaling, whereas WAVE2 modulates dorsal membrane ruffling. Furthermore, our data suggests that Tir, a protein essential for enterohemorrhagic Escherichia coli infection, might compete for Rif for interaction with the I-BAR domain of IRTKS. Based on this evidence, we propose a model in which Rho family GTPases use the I-BAR proteins, IRSp53 (also known as BAIAP2), IRTKS and Pinkbar, as a central mechanism to modulate cell morphology.

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Section: Discussionsupporting

confidence: 75%

The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

Sudhaharan

Sem

Liew

et al. 2016

Journal of Cell Science

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“…In particular, if Eps8L1 or other members of this family turn out to be more relevant partners of CD3 than Nck, the lessons learned from studies on Eps8 in regulation of epidermal growth factor receptor signaling, internalization, and trafficking (33) might provide a framework for future investigations into this question. Also, the recently revealed actin capping activity of Eps8 (34,35) could hint to alternative roles for the Eps8L1-CD3 interaction in regulation of T cell actin remodeling.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal Regulation of SH3 and SH2 Domain Binding via Tyrosine Phosphorylation of a Common Site in CD3ε

Kesti

Ruppelt

Wang

et al. 2007

The Journal of Immunology

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Recruitment of cellular signaling proteins by the CD3 polypeptides of the TCR complex mediates T cell activation. We have screened a human Src homology 3 (SH3) domain phage display library for proteins that can bind to the proline-rich region of CD3ε. This screening identified Eps8L1 (epidermal growth factor receptor pathway substrate 8-like 1) together with the N-terminal SH3 domain of Nck1 and Nck2 as its preferred SH3 partners. Studies with recombinant proteins confirmed strong binding of CD3ε to Eps8L1 and Nck SH3 domains. CD3ε bound well also to Eps8 and Eps8L3, and modestly to Eps8L2, but not detectably to other SH3 domains tested. Interestingly, binding of Nck and Eps8L1 SH3 domains was mapped to a PxxDY motif that shared its tyrosine residue (Y166) with the ITAM of CD3ε. Phosphorylation of this residue abolished binding of Eps/Nck SH3 domains in peptide spot filter assays, as well as in cells cotransfected with a dominantly active Lck kinase. TCR ligation-induced binding and phosphorylation-dependent loss of binding were also demonstrated between Eps8L1 and endogenous CD3ε in Jurkat T cells. Thus, phosphorylation of Y166 serves as a molecular switch during T cell activation that determines the capacity of CD3ε to interact with either SH3 or SH2 domain-containing proteins.

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“…More recently, it has been shown that Eps8 is a novel actin capping protein that is essential for cell motility by regulating the growth of actin filaments to generate propulsive force . The C-terminal effector region of Eps8 possesses actin filament barbed-end capping activity, recruiting Eps8 to the actin dynamic sites, such as membrane ruffles, where E3b1, Sos1 and p85 also localize (Scita et al, 2001;Innocenti et al, 2003;Croce et al, 2004;Disanza et al, 2004). Eps8 has also been shown to increase the expression and activity of focal adhesion kinase (FAK; Maa et al, 2007), which raises the possibility that Eps8 may be involved in the transduction of integrin-induced signals.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation

Yap

Jenei

Robinson³

et al. 2009

Oncogene

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Oral squamous cell carcinoma (OSCC) is a lethal disease and early death usually occurs as a result of local invasion and regional lymph node metastases. Current treatment regimens are, to a certain degree, inadequate, with a 5-year mortality rate of around 50% and novel therapeutic targets are urgently required. Using expression microarrays, we identified the eps8 gene as being overexpressed in OSCC cell lines relative to normal oral keratinocytes, and confirmed these findings using RT-PCR and western blotting. In human tissues, we found that Eps8 was upregulated in OSCC (32% of primary tumors) compared with normal oral mucosa, and that expression correlated significantly with lymph node metastasis (P ¼ 0.032), suggesting a diseasepromoting effect. Using OSCC cell lines, we assessed the functional role of Eps8 in tumor cells. Although suppression of Eps8 produced no effect on cell proliferation, both cell spreading and migration were markedly inhibited. The latter cell functions may be modulated through the small GTP-ase, Rac1 and we used pull-down assays to investigate the role of Eps8 in Rac1 signaling. We found that avb6-and a5b1-integrin-dependent activation of Rac1 was mediated through Eps8. Knockdown of either Eps8 or Rac1, inhibited integrindependent cell migration similarly and transient expression of constitutively active Rac1 restored migration of cells in which Eps8 expression had been suppressed. We also showed that knockdown of Eps8 inhibited tumor cell invasion in an organotypic model of OSCC. These data suggest that Eps8 and Rac1 are part of an integrated signaling pathway modulating integrin-dependent tumour cell motility and identify Eps8 as a possible therapeutic target.

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A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans

Cited by 112 publications

References 20 publications

The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia

Reciprocal Regulation of SH3 and SH2 Domain Binding via Tyrosine Phosphorylation of a Common Site in CD3ε

Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation

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