Vinculin regulation of F-actin bundle formation

Tolbert, Caitlin E.; Burridge, Keith; Campbell, Sharon L.

doi:10.4161/cam.23184

Cited by 29 publications

(35 citation statements)

References 55 publications

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“…Vinculin binds to transmembrane proteins with its head domain and bundles or cross-links cortical F-actin with its tail domain, and is conserved across monkey, rat, and fly (fig. S5) (16, 21). Increased vinculin expression may reinforce the cortical actin superstructure, leading to measurable changes in cortical stiffness.…”

Section: Resultsmentioning

confidence: 99%

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Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

et al. 2015

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The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts.

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Section: Resultsmentioning

confidence: 99%

“…Additionally, vinculin has been implicated in integrin- (10) and cadherin-mediated (15) mechanotransduction and actin cytoskeletal interactions (21). Cardiac-specific vinculin deletion disrupts junctions and results in sudden death or cardiomyopathy in mice (38).…”

Section: Discussionmentioning

confidence: 99%

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

et al. 2015

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“…To examine this possibility, we monitored the recruitment of binding partners to adhesion complexes formed around magnetic beads coated with fibronectin in the presence of vinculin mutants deficient in F‐actin bundling (ΔC2‐, ΔC5‐vinculin). While differences in the recruitment of select binding partners, vinexin‐α and the Arp2/3 complex, were observed, there was also a decrease in actin enrichment with these C‐terminal variants [87]. These results suggest that not only does vinculin mediate actin accumulation at adhesions through its F‐actin bundling function, but that the vinculin dimer could play a scaffolding role as well by generating a new scaffolding interface, absent in the monomer, for interaction with binding partners.…”

Section: Vinculin Bundling Of F‐actin and Its Biological Importancementioning

confidence: 96%

Vinculin and metavinculin: Oligomerization and interactions with F‐actin

2013

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a b s t r a c tVinculin, and its splice variant metavinculin, are scaffolding proteins that localize to cellular adhesions. Vinculin is a key player in mediating cell adhesion, motility, and cellular response to force. In the past decade, a number of new studies have evaluated the importance of vinculin oligomers, especially in their role of bundling F-actin. Emerging evidence also suggests that vinculin oligomerization is important for vinculin's scaffolding function. Here we describe the latest findings on vinculin's interaction with F-actin and we clarify the different known vinculin oligomers. Differences in these functions between vinculin and metavinculin provide key insights to the structure and function of these oligomers, and should guide further studies.

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“…7T), but it is expected to be forward polarized in vivo (85)(86)(87). Vinculin can directly bind to F-actin, and as a homodimer it can bundle F-actin (92). In the Simmune model, in silico activated Vcl refers solely to its actin bundling function.…”

Section: Figmentioning

confidence: 99%

Targeted Proteomics-Driven Computational Modeling of Macrophage S1P Chemosensing

Manes

Angermann

Koppenol-Raab

et al. 2015

Molecular & Cellular Proteomics

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Osteoclasts are monocyte-derived multinuclear cells that directly attach to and resorb bone. Sphingosine-1-phosphate (S1P) 1 regulates bone resorption by functioning as both a chemoattractant and chemorepellent of osteoclast precursors through two G-protein coupled receptors that antagonize each other in an S1P-concentration-dependent manner. To quantitatively explore the behavior of this chemosensing pathway, we applied targeted proteomics, transcriptomics, and rule-based pathway modeling using the Simmune toolset. RAW264.7 cells (a mouse monocyte/macrophage cell line) were used as model osteoclast precursors, RNA-seq was used to identify expressed target proteins, and selected reaction monitoring (SRM) mass spectrometry using internal peptide standards was used to perform absolute abundance measurements of pathway proteins. The resulting transcript and protein abundance values were strongly correlated. Measured protein abundance values, used as simulation input parameters, led to in silico pathway behavior matching in vitro measurements. Moreover, once model parameters were established, even simulated responses toward stimuli that were not used for parameterization were consistent with experimental findings. These findings demonstrate the feasibility and value of combining targeted mass spectrometry with pathway modeling for advancing biological insight. Molecular & Cellular Proteomics 14: 10.1074/mcp.M115.048918, 2661-2681, 2015.Chemotaxis is defined as directed movement of a cell (or of an organism) resulting from stimulation by a chemokine or other chemotactic chemical. Eukaryotic cells employ intricate intracellular pathways to sense concentration differences of chemoattractants at their surface and move along such gradients using multiple synchronized cellular processes, including cell protrusion and adhesion at the leading end, de-adhesion at the trailing end, and mechanical force generation at both the leading and trailing ends (1-4).Activation of chemotactic receptors through chemoattractant concentration gradients results in nonuniform intracellular signaling responses that depend on numerous feedback mechanisms (5-7). Downstream, F-actin synthesis at the leading end causes the formation of cell protrusions (for example, filopodia, lamellipodia, and lamellae) that, in concert with actomyosin contraction, generates force at both the leading and trailing ends (8 -10). Chemotactic traction is produced by cell protrusions interacting with a confined environment and/or by adhesions that bind to the extracellular matrix and/or to cell adhesion molecules (11).Chemotaxis plays a major role in a wide range of physiological and pathophysiological processes. Sphingosine-1-phosphate (S1P), a phosphosphingolipid, mediates chemotaxis of many circulating cell types, including osteoclast precursors (OPs) (12)(13)(14). Osteoclasts are monocyte-derived multinuclear cells that directly attach to the bone matrix and resorb bone. They are solely responsible for bone resorption, and their misregulated activity has been imp...

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Vinculin regulation of F-actin bundle formation

Cited by 29 publications

References 55 publications

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

Vinculin and metavinculin: Oligomerization and interactions with F‐actin

Targeted Proteomics-Driven Computational Modeling of Macrophage S1P Chemosensing

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