Ena/VASP: proteins at the tip of the nervous system

Drees, Frauke; Gertler, Frank B.

doi:10.1016/j.conb.2008.05.007

Cited by 109 publications

(109 citation statements)

References 65 publications

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“…The stimulation of human neutrophils by a chemoattractant induces the PKA-dependent phosphorylation of VASP at Ser157 (21). VASP also plays a critical role in neuronal function by modulating the initiation of neurites and the outgrowth and guidance of axons (22). The negative regulatory function of VASP phosphorylation in cell migration was also suggested (23).…”

Section: Discussionmentioning

confidence: 99%

β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

Goncharova

Goncharov

Zhao

et al. 2012

Am J Respir Cell Mol Biol

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Severe asthma manifests as airway remodeling and irreversible airway obstruction, in part because of the proliferation and migration of human airway smooth muscle (HASM) cells. We previously reported that cyclic adenosine monophosphate-mobilizing agents, including b 2 -adrenergic receptor (b 2 AR) agonists, which are mainstay of asthma therapy, and prostaglandin E2 (PGE2), inhibit the migration of HASM cells, although the mechanism for this migration remains unknown. Vasodilator-stimulated phosphoprotein (VASP), an anticapping protein, modulates the formation of actin stress fibers during cell motility, and is negatively regulated by protein kinase A (PKA)-specific inhibitory phosphorylation at serine 157 (Ser157). Here, we show that treatment with b 2 AR agonists and PGE2 induces the PKA-dependent phosphorylation of VASP and inhibits the migration of HASM cells. The stable expression of PKA inhibitory peptide and the small interfering (si) RNA-induced depletion of VASP abolish the inhibitory effects of albuterol and PGE2 on the migration of HASM cells. Importantly, prolonged treatment with albuterol prevents the agonist-induced phosphorylation of VASP at Ser157, and reverses the inhibitory effects of albuterol and formoterol, but not PGE2, on the basal and PDGF-induced migration of HASM cells. Collectively, our data demonstrate that b 2 AR agonists selectively inhibit the migration of HASM cells via a b 2 AR/PKA/ VASP signaling pathway, and that prolonged treatment with albuterol abolishes the inhibitory effect of b-agonists on the phosphorylation of VASP and migration of HASM cells because of b 2 AR desensitization.Keywords: airway hyperresponsiveness; b 2 -adrenergic receptor desensitization; protein kinase A; albuterol; formoterol Human airway smooth muscle (HASM) hyperplasia and remodeling are characteristic features of airways that contribute to their irreversible obstruction in patients with severe asthma. Accumulating evidence suggests that cell migration contributes to airway smooth muscle hyperplasia and remodeling (1, 2). Recently, the migration of airway smooth muscle (ASM) cells toward the epithelium and lumen of the airway was reported as a potential contributor to the increased smooth muscle mass in patients with asthma (3, 4). Further, cell-culture studies show that mitogens and inflammatory mediators involved in asthma pathogenesis and pharmacological agents in current used for the treatment of asthma modulate the migration of ASM cells (1,5,6). Taken together, these studies suggest that the migration of ASM cells contributes to ASM cell hyperplasia under asthmarelated conditions (1). Although the role of HASM hyperplasia in asthma is well established, the molecular mechanisms regulating the migration of HASM cells under asthma-related conditions are poorly understood (1).Evidence demonstrates that cyclic adenosine monophosphate (cAMP)-inducing agents, including the long-acting b 2 -adrenergic receptor (b 2 AR) agonist formoterol, inhibit the agonist-dependent migration of ASM cells (5, 7). We p...

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Section: Discussionmentioning

confidence: 99%

β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

Goncharova

Goncharov

Zhao

et al. 2012

Am J Respir Cell Mol Biol

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“…Activity of the actin-severing proteins gelsolin and cofilin is reduced in Srf mutants and might thereby disable actin filament turn-over (Alberti et al, 2005). Triple Mena/Vasp/ Evl mutant neurons (Kwiatkowski et al, 2007), key molecules of filopodia formation (Drees and Gertler, 2008), resemble Srf Ϫ/Ϫ neurons suggesting that Ena/Vasp genes might be potential SRF target genes or upstream regulators. .…”

Section: Actin Modulates Neuronal Morphology By Nuclear Gene Expressionmentioning

confidence: 99%

A Nuclear Actin Function Regulates Neuronal Motility by Serum Response Factor-Dependent Gene Transcription

Stern

Debre²,

Stritt³

et al. 2009

J. Neurosci.

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Neuronal motility relies on actin treadmilling. In addition to regulating cytoskeletal dynamics in the cytoplasm, actin modulates nuclear gene expression. We present a hitherto unappreciated cross talk of actin signaling with gene expression governing neuronal motility. Toward this end, we used a novel approach using mutant actins either favoring (G15S) or inhibiting (R62D) F-actin assembly. Overexpressing these mutant actins in mouse hippocampal neurons not only modulated growth-cone function but also neurite elongation, which was ambiguous by traditional pharmacological interference. G15S actin enhanced neurite outgrowth and filopodia number. In contrast, R62D reduced neurite length and impaired growth-cone filopodia formation. Growth-cone collapse induced by ephrin-As, a family of repulsive axon guidance molecules, is impaired upon R62D expression, resulting in perseverance of ring-shaped F-actin filaments. R62D-induced phenotypes strongly resemble neurons lacking SRF (Serum Response Factor). SRF controls gene transcription of various actin isoforms (e.g., Actb, Acta1) and actin-binding proteins (e.g., Gsn) and is the archetypical transcription factor to study actin interplay with transcription. We show that neuronal motility evoked by these actin mutants requires SRF activity. Further, constitutively active SRF partially rescues R62D-induced phenotypes. Conversely, actin signaling regulates neuronal SRF-mediated gene expression. Notably, a nucleus-resident actin (R62D NLS ) also regulates SRF's transcriptional activity. Moreover, R62D NLS decreases neuronal motility similar to the cytoplasmic R62D actin mutant although R62D NLS has no access to cytoplasmic actin dynamics. Thus, herein we provide first evidence that neuronal motility not only depends on cytoplasmic actin dynamics but also on the availability of actin to modulate nuclear functions such as gene transcription.

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“…Dictyostelium Dia2 is enriched at the tips of filopodia, and is needed for formation and maintenance of filopodia (Schirenbeck et al, 2005); the Dia2 protein is similarly enriched at both lamellipodia and filopodia in mammalian cells (Yang et al, 2007). Ena-and/or vasodilator-stimulated phosphoprotein (VASP)-null neurons are defective in neurite initiation, but can be rescued by restoring filopodia formation through ectopic expression of mammalian Dia2 (Drees and Gertler, 2008). An alternative route for generating new barbed ends involves the assembly of an actin branch on an existing filament -this occurs through the activities of the Wiskott-Aldrich syndrome protein (WASP) and WASP-family verprolinhomologous (WAVE) proteins, as described in the next section.…”

Section: Actin Polymerization I: Promoting F-actin Nucleation Throughmentioning

confidence: 99%

Rho GTPases and their role in organizing the actin cytoskeleton

Sit¹,

Manser

2011

Journal of Cell Science

425

388

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Ena/VASP: proteins at the tip of the nervous system

Cited by 109 publications

References 65 publications

β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

A Nuclear Actin Function Regulates Neuronal Motility by Serum Response Factor-Dependent Gene Transcription

Rho GTPases and their role in organizing the actin cytoskeleton

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Ena/VASP: proteins at the tip of the nervous system

Cited by 109 publications

References 65 publications

β2-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

β2-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

A Nuclear Actin Function Regulates Neuronal Motility by Serum Response Factor-Dependent Gene Transcription

Rho GTPases and their role in organizing the actin cytoskeleton

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β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein