VAMP-7 links granule exocytosis to actin reorganization during platelet activation

Koseoglu, Secil; Peters, Christian; Fitch-Tewfik, Jennifer L.; Aisiku, Omozuanvbo; Danglot, Lydia; Galli, Thierry; Flaumenhaft, Robert

doi:10.1182/blood-2014-12-618744

Cited by 51 publications

(55 citation statements)

References 62 publications

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“…7B, panel b), suggesting that while Arp2/3 was important for filopodia formation, branched actin networks were less essential once the syncytium had been established. Whether Arp2/3 participates in skeletogenesis through its well-established roles in membrane trafficking remains to be determined (Gasman et al, 2004; Koseoglu et al, 2015; Tran et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

Sepúlveda-Ramírez

Toledo-Jacobo

Henson

et al. 2018

Developmental Biology

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In the sea urchin embryo, gastrulation is characterized by the ingression and directed cell migration of primary mesenchyme cells (PMCs), as well as the primary invagination and convergent extension of the endomesoderm. Like all cell shape changes, individual and collective cell motility is orchestrated by Rho family GTPases and their modulation of the actomyosin cytoskeleton. And while endomesoderm specification has been intensively studied in echinoids, much less is known about the proximate regulators driving cell motility. Toward these ends, we employed anti-sense morpholinos, mutant alleles and pharmacological inhibitors to assess the role of Cdc42 during sea urchin gastrulation. While inhibition of Cdc42 expression or activity had only mild effects on PMC ingression, PMC migration, alignment and skeletogenesis were disrupted in the absence of Cdc42, as well as elongation of the archenteron. PMC migration and patterning of the larval skeleton relies on the extension of filopodia, and Cdc42 was required for filopodia in vivo as well as in cultured PMCs. Lastly, filopodial extension required both Arp2/3 and formin actin-nucleating factors, supporting models of filopodial nucleation observed in other systems. Together, these results suggest that Cdc42 plays essential roles during PMC cell motility and organogenesis.

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Section: Discussionmentioning

confidence: 99%

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

Sepúlveda-Ramírez

Toledo-Jacobo

Henson

et al. 2018

Developmental Biology

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“…SNAREs and Munc13-4 are required for platelet granule secretion (13–16, 18, 19, 24, 26), but little is known about the step-by-step order of events that culminate in Ca 2+ -activated fusion of granules with the plasma membrane. Previous work from our lab showed that platelet dense granule secretion is ablated in the absence of Munc13-4 while α-granule and lysosomal secretion persist at attenuated rates (24).…”

Section: Discussionmentioning

confidence: 99%

“…Platelets contain a variety of v-SNAREs and t-SNAREs, but previous studies from our laboratory and others suggest that VAMP8 acts as a primary v-SNARE for granule secretion and heterodimer complexes comprising syntaxin-11 and SNAP-23 are key t-SNARE complexes (13–17). Recently, VAMP7 and Syntaxin 8 have been shown to also contribute to platelet exocytosis (18, 19). While SNARE proteins are the core membrane fusion machinery, a host of regulatory proteins affect the timing, location, and Ca 2+ -sensitivity of secretion.…”

Section: Introductionmentioning

confidence: 99%

Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

Chicka

Ren

Richards

et al. 2016

Biochemical Journal

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The Munc13 family of exocytosis regulators has multiple Ca2+-binding, C2 domains. Here, we probed the mechanism by which Munc13-4 regulates in vitro membrane fusion and platelet exocytosis. We show that Munc13-4 enhances in vitro SNARE-dependent, proteoliposome fusion in a Ca2+- and phosphatidylserine (PS)-dependent manner that was independent of SNARE concentrations. Munc13-4-SNARE interactions, under the conditions used, were minimal in the absence or presence of Ca2+. However, Munc13-4 was able to bind and cluster liposomes harboring PS in response to Ca2+. Interestingly, Ca2+-dependent liposome binding/clustering and enhancement of proteoliposome fusion required both Munc13-4 C2 domains, but only the Ca2+-liganding aspartate residues of the C2B domain. Analytical ultracentrifugation measurements indicated that, in solution, Munc13-4 was a monomeric prolate ellipsoid with dimensions consistent with a molecule that could bridge two fusing membranes. To address the potential role of Munc13-4 as a tethering protein in platelets, we examined mepacrine-stained, dense granule mobility and secretion in platelets from wild-type and Munc13-4 null (Unc13dJinx) mice. In the absence of Munc13-4, dense granules were highly mobile in both resting and stimulated platelets, and stimulation-dependent granule release was absent. These observations suggest that dense granules are stably docked in resting platelets awaiting stimulation and that Munc13-4 plays a vesicle-stabilizing or tethering role in resting platelets and also in activated platelets in response to Ca2+. In summary, we show that Munc13-4 conveys Ca2+ sensitivity to platelet SNARE-mediated membrane fusion and reveal a potential mechanism by which Munc13-4 bridges and stabilizes apposing membranes destined for fusion. (246 words)

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“…Loss of Arp2/3 function can have severe consequences, as illustrated by the embryonic lethality of mice homozygous for an ARP3 hypomorph (38). In hemostasis, the Arp2/3 complex is necessary for actin-dependent platelet cytoskeletal remodeling events, which are essential for platelet activation and degranulation (37,39,40). The Actr2 +/G mutation results in a p.R258G substitution in exon 7 of Actr2 at a highly conserved amino acid position, with arginine present at this position for all 60 available vertebrate sequences (https://genome.ucsc.edu), as well as in plants and fungi (Fig.…”

mentioning

confidence: 99%

Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci

Westrick

Tomberg

Siebert

et al. 2017

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

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Factor V Leiden (F5 L ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized N-ethyl-Nnitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for) and haploinsufficient for tissue factor pathway inhibitor (Tfpi ), suggesting that Actr2 p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism of action for Actr2 p.R258G. Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5 L and also suggest a role for Actr2 in this process.venous thromboembolism | Factor V Leiden | ENU mutagenesis | tissue factor pathway inhibitor | genetic screen

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VAMP-7 links granule exocytosis to actin reorganization during platelet activation

Abstract: Key Points VAMP-7 functions in platelet granule exocytosis and spreading. VAMP-7 associates with VARP and Arp2/3, thereby linking granule exocytosis and actin reorganization.

Cited by 51 publications

References 62 publications

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion

Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci

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