The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops

Menacho‐Marquez, Mauricio; García‐Escudero, Ramón; Ojeda, Virginia; Abad, Antonio; Delgado, Pilar; Costa, Clotilde; Ruíz, Sergio; Alarcón, Balbino; Paramio, Jesús M.; Bustelo, Xosé R.

doi:10.1371/journal.pbio.1001615

Cited by 65 publications

(83 citation statements)

References 53 publications

(71 reference statements)

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“…VAV2 is an activator (exchange factor) of Rho GTPases42 and the latter have important roles in different steps of junction assembly, maturation and disruption. The partnership of VAV2 and TRIP10 identified here is functionally and clinically relevant, as both have important functions in epithelial differentiation and morphogenesis43444546, and participate in oncogenic pathways leading to cell invasion3247484950.…”

Section: Discussionmentioning

confidence: 88%

Defining functional interactions during biogenesis of epithelial junctions

et al. 2016

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In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.

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Section: Discussionmentioning

confidence: 88%

Defining functional interactions during biogenesis of epithelial junctions

et al. 2016

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“…The relative TGF-β mRNA levels were determined using TGF-β1 and GAPDH primers previously reported [53, 54]. The skin samples were immediately frozen in liquid nitrogen and stored overnight at −80°C.…”

Section: Methodsmentioning

confidence: 99%

Optimized polymeric film-based nitric oxide delivery inhibits bacterial growth in a mouse burn wound model

Brisbois

Bayliss

et al. 2014

Acta Biomaterialia

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Nitric oxide (NO) has many biological roles (e.g., antimicrobial agent, promoter of angiogenesis, prevention of platelet activation, etc.) that make NO releasing materials desirable for a variety of biomedical applications. Localized NO release can be achieved from biomedical grade polymers doped with diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) and poly(lactic-co-glycolic acid) (PLGA). In this study, the optimization of this chemistry to create film/patches that can be used to decrease microbial infection at wound sites is examined. Two polyurethanes with different water uptakes (Tecoflex SG-80A (6.2 ± 0.7 wt %) and Tecophillic SP-60D-20 (22.5 ± 1.1 wt%)) were doped with 25 wt% DBHD/N2O2 and 10 wt% of PLGA with various hydrolysis rates. Films prepared with the polymer that has the higher water uptake (SP-60D-20) were found to have higher NO release and for a longer duration than the polyurethane with lower water uptake (SG-80A). The more hydrophilic polymer enhances the hydrolysis rate of the PLGA additive, thereby providing a more acidic environment that increases the rate of NO release from the NO donor. The optimal NO releasing and control SG-80A patches were then applied to scald burn wounds that were infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24 h (~4 log reduction). The NO release patches are also able to reduce the TGF-β levels, in comparison to controls, which can enhance reepithelialization, decrease scarring, and reduce migration of bacteria. The combined DBHD/N2O2 and PLGA-doped polymer patches, which could be replaced periodically throughout the wound healing process, demonstrate the potential to reduce risk of bacterial infection and promote the overall wound healing process.

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“…Focus formation assays were performed with NIH3T3 cells as previously described (28,60). GTPase-linked immunosorbent assays were performed with a commercial kit (Cytoskeleton), as described previously (19,23).…”

Section: Biological Assaysmentioning

confidence: 99%

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins

et al. 2014

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Vav proteins are phosphorylation-dependent guanine nucleotide exchange factors (GEFs) that catalyze the activation of members of the Rho family of guanosine triphosphatases (GTPases). The current regulatory model holds that the nonphosphorylated, catalytically inactive state of these GEFs is maintained by intramolecular interactions among the amino-terminal domains and the central catalytic core, which block the binding of Vav proteins to GTPases. We showed that this autoinhibition is mechanistically more complex, also involving the bivalent association of the carboxyl-terminal Src homology 3 (SH3) region of Vav with its catalytic and pleckstrin homology (PH) domains. Such interactions occurred through proline-rich region-independent mechanisms. Full release from this double-locked state required synergistic weakening effects from multiple phosphorylated tyrosine residues, thus providing an optimized system to generate gradients of Vav GEF activity depending on upstream signaling inputs. This mechanism is shared by mammalian and Drosophila melanogaster Vav proteins, suggesting that it may be a common regulatory feature for this protein family.

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The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops

Abstract: Rho GEFs Vav2 and Vav3 regulate pro-tumorigenic autocrine/paracrine signals in keratinocytes and are dispensable for skin homeostasis.

Cited by 65 publications

References 53 publications

Defining functional interactions during biogenesis of epithelial junctions

Defining functional interactions during biogenesis of epithelial junctions

Optimized polymeric film-based nitric oxide delivery inhibits bacterial growth in a mouse burn wound model

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins

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