Molecular Basis for the Dual Function of Eps8 on Actin Dynamics: Bundling and Capping

Hertzog, Maud; Milanesi, Francesca; Hazelwood, Larnele; Disanza, Andrea; Liu, Hongjun; Perlade, Emilie; Malabarba, Maria Grazia; Pasqualato, Sebastiano; Maiolica, Alessio; Confalonieri, Stefano; Clainche, Christophe Le; Offenhäuser, Nina; Block, Jennifer; Rottner, Klemens; Fiore, Pier Paolo Di; Carlier, Marie‐France; Volkmann, Niels; Hanein, Dorit; Scita, Giorgio

doi:10.1371/journal.pbio.1000387

Cited by 100 publications

(131 citation statements)

References 76 publications

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“…Consistently, EPS8, in vivo, is required for optimal actin-based motility impacting migratory properties of different cells (Frittoli et al, 2011). Furthermore, EPS8 regulates the proper architectural organization of actin-based structures, including intestinal microvilli and stereocilia (Disanza et al, 2006;Hertzog et al, 2010;Tocchetti et al, 2010;Manor et al, 2011). One ; the data are representative of five independent experiments.…”

Section: Introductionmentioning

confidence: 74%

“…EPS8 also directly binds to actin filaments controlling the rate of polymerization/depolymerization by capping the fast-growing ends of filaments Disanza et al, 2004Disanza et al, , 2006Hertzog et al, 2010). Consistently, EPS8, in vivo, is required for optimal actin-based motility impacting migratory properties of different cells (Frittoli et al, 2011).…”

Section: Introductionmentioning

confidence: 83%

“…Indeed, ECs expressing an EPS8 mutant devoid of actin capping and bundling functions (Hertzog et al, 2010) showed a YAP activity almost equal to EPS8 + -expressing cells as measured by serine 127 phosphorylation levels (Fig. 8 A) and by the induction of target gene expression (Fig.…”

Section: α-Catenin At Ajsmentioning

confidence: 94%

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The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

Giampietro¹,

Disanza²,

Bravi³

et al. 2016

J Gen Physiol

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 83%

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The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

Giampietro¹,

Disanza²,

Bravi³

et al. 2016

J Gen Physiol

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“…Secondary structure elements are common to several known barbed end cappers. Binding of an amphipathic ␣-helix to a hydrophobic pocket between subdomains 1 and 3 at the barbed face of actin supports the capping activity of Eps8 (35), gelsolin (36), CapZ (37), twinfilin (38), capping protein (39) as well as the multiple activities of ␤-thymosin/WH2 domains (40 -43). The protein VASP also binds both to the sides of filaments via an F-actin binding region and to the barbed face of actin via a WH2 domain (44), which may assist its processive tracking of barbed ends (45,46).…”

Section: Iqgap1 Interacts With Both the Sides And The Barbed Ends Ofmentioning

confidence: 98%

The IQGAP1 Protein Is a Calmodulin-regulated Barbed End Capper of Actin Filaments

Pelikan-Conchaudron¹,

Clainche

Didry

et al. 2011

Journal of Biological Chemistry

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IQGAP1 is a large modular protein that displays multiple partnership and is thought to act as a scaffold in coupling cell signaling to the actin and microtubule cytoskeletons in cell migration, adhesion, and cytokinesis. However the molecular mechanisms underlying the activities of IQGAP1 are poorly understood in part because of its large size, poor solubility and lack of functional assays to challenge biochemical properties in various contexts. We have purified bacterially expressed recombinant human IQGAP1. The protein binds Cdc42, Rac1, and the CRIB domain of N-WASP in a calmodulin-sensitive fashion. We further show that in addition to bundling of filaments via a single N-terminal calponin-homology domain, IQGAP1 actually regulates actin assembly. It caps barbed ends, with a higher affinity for ADP-bound terminal subunits (K B ‫؍‬ 4 nM). The barbed end capping activity is inhibited by calmodulin, consistent with calmodulin binding to IQGAP1 with a K C of 40 nM, both in the absence and presence of Ca 2؉ ions. The barbed end capping activity resides in the C-terminal half of IQGAP1. It is possible that the capping activity of IQGAP1 accounts for its stimulation of cell migration. We further find that bacterially expressed recombinant IQGAP1 fragments easily co-purify with nucleic acids that turn out to activate N-WASP protein to branch filaments with Arp2/3 complex. The present results open perspectives for tackling the function of IQGAP1 in more complex reconstituted systems.

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“…Depending on their association with other signal transducers, they act directly on actin by binding to it and by modulating actin bundling and/or actin barbed-end capping activities (32)(33)(34). Notably, Eps8L2 lacks IRSp53 binding, which is essential in Eps8 for relieving inhibition of actin-bundling activity (33).…”

Section: Loss Of Eps8l2 Is Associated With Severe Progressive Hearingmentioning

confidence: 99%

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Furness

Johnson

Manor

et al. 2013

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

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Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 nullmutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss.deafness | sensory system | ion channel H earing and balance depend on the transduction of mechanical stimuli into electrical signals. Transduction involves activation of mechanically gated ion channels near the tips of the stereocilia, specialized microvilli that form the hair bundles that project from the surface of sensory hair cells (1). Stereocilia have a cytoskeletal core composed of tightly packed, cross-linked, and uniformly polarized actin filaments (2, 3). Stereociliary length is regulated to ensure the characteristic staircase-like structure of each bundle, whose overall size and shape depends on location along the sensory organ (4). In the mammalian cochlea, hair bundles usually include three rows of stereocilia coupled by several types of extracellular links (2, 5). The embryonic and postnatal development of the bundle involves elongation and thickening of stereocilia, as well as elimination of redundant stereocilia (4, 5).In the adult cochlea, the height of stereocilia within each row is similar, not only within a single hair bundle but also between the bundles of adjacent hair cells, indicating a sophisticated level of control over growth (5, 6). Stereociliary growth and maintenance involves actin-binding proteins such as espin (7,8), plastin (9), twinfilin 2 (10), gelsolin (11), and unconventional myosin motors including myosin XVa (12) and myosin IIIa (13). Currently, we do not have a complete molecular understanding of hair bundle structure or how its growth and maintenance are controlled. Recently, we showed that epidermal growth factor receptor pathway substrate 8 (Eps8) (14) is located ...

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Molecular Basis for the Dual Function of Eps8 on Actin Dynamics: Bundling and Capping

Abstract: The unusual dual functions of the actin-binding protein EPS8 as an actin capping and actin bundling factor are mapped to distinct structural features of the protein and to distinct physiological activities in vivo.

Cited by 100 publications

References 76 publications

The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

The IQGAP1 Protein Is a Calmodulin-regulated Barbed End Capper of Actin Filaments

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

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