Function and regulation of Ena/VASP proteins

Kwiatkowski, Adam V.; Gertler, Frank B.; Loureiro, Joseph

doi:10.1016/s0962-8924(03)00130-2

Cited by 151 publications

(141 citation statements)

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“…Mena was the first protein identified to interact with the WW domain of Fe65 (16). Mena belongs to a small family of proteins involved in the control of cell movement and morphology and in chemotactic responses (37). It was demonstrated that Fe65 and APP are present in dynamic adhesion complexes present on the surface of the cells and that their overexpression causes the acceleration of cell migration (38).…”

Section: Fe65 Cytoskeleton Remodeling and Cell Movementmentioning

confidence: 99%

Fe65 matters: New light on an old molecule

et al. 2012

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SummaryThe discovery that the main constituents of amyloid deposits, characteristic of Alzheimer neuropathology, derive from the proteolytic processing of the membrane precursor amyloid precursor protein (APP) is one of the milestones of the research history of this disease. Despite years of intense studies, the functions of APP and of its amyloidogenic processing are still under debate. One focus of these studies was the complex network of protein-protein interactions centered at the cytosolic domain of APP, which suggests the involvement of APP in a lively signaling pathway. Fe65 was the first protein to be demonstrated to interact with the APP cytodomain. Starting from this observation, a large body of data has been gathered, indicating that Fe65 is an adaptor protein, which binds numerous proteins, further than APP. Among these proteins, the crosstalk with Mena, mDab, and Abl suggested the involvement of the Fe65-APP complex in the regulation of cell motility, with a relevant role in differentiation and development. Other partners, like the histone acetyltransferase Tip60, indicated the possibility that the nuclear fraction of Fe65 could be involved in gene regulation and/or DNA repair.2012 IUBMB IUBMB Life, 64(12): 936-942, 2012

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Section: Fe65 Cytoskeleton Remodeling and Cell Movementmentioning

confidence: 99%

Fe65 matters: New light on an old molecule

et al. 2012

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“…41 In D. discoideum, the homolog DdVASP was found. 39,41 DdVASP expression occurs in vegetative cells and increases with starvation peaking at 8 h. 39 Phosphorylation of VASP is important for its cortical localization and interaction with WASP and WIPa that are key regulators of F-actin organization. 42 Lin and co-workers 42 showed that VASP phosphorylation still occurs in Dictyostelium null strains of the PKA catalytic domain ( pka-cat À ) and of guanylyl cyclases (sgc/gca À ).…”

Section: Discussionmentioning

confidence: 99%

Intracellular photoactivation of caged cGMP induces myosin II and actin responses in motile cells

et al. 2013

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Cyclic GMP (cGMP) is a ubiquitous second messenger in eukaryotic cells. It is assumed to regulate the association of myosin II with the cytoskeleton of motile cells. When cells of the social amoeba Dictyostelium discoideum are exposed to chemoattractants or to increased osmotic stress, intracellular cGMP levels rise, preceding the accumulation of myosin II in the cell cortex. To directly investigate the impact of intracellular cGMP on cytoskeletal dynamics in a living cell, we released cGMP inside the cell by laser-induced photo-cleavage of a caged precursor. With this approach, we could directly show in a live cell experiment that an increase in intracellular cGMP indeed induces myosin II to accumulate in the cortex. Unexpectedly, we observed for the first time that also the amount of filamentous actin in the cell cortex increases upon a rise in the cGMP concentration, independently of cAMP receptor activation and signaling. We discuss our results in the light of recent work on the cGMP signaling pathway and suggest possible links between cGMP signaling and the actin system. Insight, innovation, integrationSecond messengers like cGMP play a central role in the regulatory pathways of living cells. Here, we demonstrate that an increase in intracellular cGMP can trigger not only myosin II but also actin responses in motile amoeboid cells. In previous studies, an increase in intracellular cGMP was induced indirectly via membrane receptor stimulation. In the present work, we employ, for the first time, the direct light-induced release of cGMP from a caged precursor to raise the cytosolic cGMP level in Dictyostelium cells that carry fluorescent markers for filamentous actin and myosin II. Based on this advanced combination of live cell photo-uncaging and multi-color confocal microscopy, we could identify a link between cGMP and actin dynamics in motile amoeboid cells.

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Section: Introductionmentioning

confidence: 99%

“…Recent work suggests that Abl also influences microtubule polymerization in the axon growth cone via interactions with Orbit and that a mouse Abl-related protein, Arg, can crosslink F-actin with microtubules in the cell periphery (Lee et al, 2004;Miller et al, 2004). In part, the influence of Abl on F-actin-dependent processes is mediated by its regulatory interaction with Ena/VASP proteins, which can modulate actin filament length, branching pattern, and bundle formation (reviewed by Krause et al, 2003;Kwiatkowski et al, 2003). Ena/VASP proteins have three conserved regions.…”

Section: Introductionmentioning

confidence: 99%

“…It can also bind Abl and other SH3-domain proteins. The C-terminal EVH2 domain (226 amino acids, Gertler et al, 1996) has both G-and F-actin binding sites and has been shown to mediate Ena/VASP multimerization (reviewed by Krause et al, 2003;Kwiatkowski et al, 2003).In Drosophila development, Ena and Abl are known to have an antagonistic relationship. Zygotic mutations in the ena or Abl gene cause axon growth-cone guidance defects and lethality, but normal axon guidance and viability can be restored by combining ena and Abl mutations (reviewed by Krause et al, 2003).…”

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Abl Tyrosine Kinase and Its Substrate Ena/VASP Have Functional Interactions with Kinesin-1

Martin

Ahern-Djamali

Hoffmann

et al. 2005

MBoC

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Relatively little is known about how microtubule motors are controlled or about how the functions of different cytoskeletal systems are integrated. A yeast two-hybrid screen for proteins that bind to Drosophila Enabled (Ena), an actin polymerization factor that is negatively regulated by Abl tyrosine kinase, identified kinesin heavy chain (Khc), a member of the kinesin-1 subfamily of microtubule motors. Coimmunoprecipitation from Drosophila cytosol confirmed a physical interaction between Khc and Ena. Kinesin-1 motors can carry organelles and other macromolecular cargoes from neuronal cell bodies toward terminals in fast-axonal-transport. Ena distribution in larval axons was not affected by mutations in the Khc gene, suggesting that Ena is not itself a fast transport cargo of Drosophila kinesin-1. Genetic interaction tests showed that in a background sensitized by reduced Khc gene dosage, a reduction in Abl gene dosage caused distal paralysis and axonal swellings. A concomitant reduction in ena dosage rescued those defects. These results suggest that Ena/VASP, when not inhibited by the Abl pathway, can bind Khc and reduce its transport activity in axons. INTRODUCTIONThe activities of the F-actin and microtubule cytoskeletons are linked in cellular processes such as secretion, cytokinesis, and axon outgrowth, but relatively little is known about mechanisms that coordinate the activities of the two filament systems. The nonreceptor tyrosine kinase Abl, aberrant forms of which are implicated in human leukemia, influences axon outgrowth and other F-actin-dependent processes (Woodring et al., 2003;Hernandez et al., 2004). Recent work suggests that Abl also influences microtubule polymerization in the axon growth cone via interactions with Orbit and that a mouse Abl-related protein, Arg, can crosslink F-actin with microtubules in the cell periphery (Lee et al., 2004;Miller et al., 2004). In part, the influence of Abl on F-actin-dependent processes is mediated by its regulatory interaction with Ena/VASP proteins, which can modulate actin filament length, branching pattern, and bundle formation (reviewed by Krause et al., 2003;Kwiatkowski et al., 2003). Ena/VASP proteins have three conserved regions. The N-terminal EVH1 domain (133 amino acids, Gertler et al., 1996) can bind the focal-adhesion proteins vinculin and zyxin, as well as the growth-cone guidance receptor Robo/ Sax3. The central proline-rich region can bind profilin, which facilitates the addition of G-actin monomers to F-actin plusends. It can also bind Abl and other SH3-domain proteins. The C-terminal EVH2 domain (226 amino acids, Gertler et al., 1996) has both G-and F-actin binding sites and has been shown to mediate Ena/VASP multimerization (reviewed by Krause et al., 2003;Kwiatkowski et al., 2003).In Drosophila development, Ena and Abl are known to have an antagonistic relationship. Zygotic mutations in the ena or Abl gene cause axon growth-cone guidance defects and lethality, but normal axon guidance and viability can be restored by combining ena and Ab...

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Function and regulation of Ena/VASP proteins

Cited by 151 publications

References 63 publications

Fe65 matters: New light on an old molecule

Fe65 matters: New light on an old molecule

Intracellular photoactivation of caged cGMP induces myosin II and actin responses in motile cells

Abl Tyrosine Kinase and Its Substrate Ena/VASP Have Functional Interactions with Kinesin-1

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