Ena/VASP regulates mDia2-initiated filopodial length, dynamics, and function

Barzik, Melanie; McClain, Leslie Marie; Gupton, Stephanie L.; Gertler, Frank B.

doi:10.1091/mbc.e14-02-0712

Cited by 78 publications

(91 citation statements)

References 105 publications

(114 reference statements)

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“…Nonetheless, based on the varying endothelial barrier properties and adhesion molecules used for extravasation into different tissues, it is possible that the Ena/ VASP family may have a more or less profound impact on trafficking to different anatomical sites. The observation that deletion of EVL and VASP impaired activated T-cell trafficking in vivo is consistent with the literature implicating Ena/VASP proteins in cellular motility (27,(47)(48)(49)(50)(51). Although we identified reduced actin polymerization in response to chemokine triggering in activated EVL/VASP dKO T cells, surprisingly we found no major effect on activated T-cell chemotaxis or crawling in vitro.…”

Section: Discussionsupporting

confidence: 92%

“…This localization pattern is consistent with a role in migration and adhesion. Fibroblasts lacking EVL and VASP produce shorter filopodia, and a slower-moving lamellipodium, which paradoxically leads to enhanced fibroblast motility (26,27). Platelets from VASP-knockout mice demonstrate enhanced vascular adhesion (28), whereas inside-out signaling through β2 integrins is impaired in VASP-deficient neutrophils (29).…”

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confidence: 99%

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Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration

Estin

Thompson

Traxinger

et al. 2017

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

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Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.A ctivated T-cell trafficking across the vascular endothelium is essential for ongoing immune surveillance of tissues and for effective immune responses to conditions such as infection and cancer. Conversely, in situations of immune dysregulation, inhibition of self-reactive T-cell trafficking represents a promising target for therapeutic immunomodulation. Disruption of these pathways, such as by antibody blockade of α4 integrins, is a highly effective approach to immunomodulation (1, 2). However, the molecular mechanisms by which chemokine receptor and adhesion molecule signaling induce the T-cell cytoskeletal machinery to promote extravasation are not yet fully elucidated.Transendothelial migration (TEM), the process by which T cells extravasate from the blood into tissues, is characterized by four distinct steps: rolling along the vascular wall, arrest or adhesion, intravascular crawling, and diapedesis across the endothelial barrier (3). Surface adhesion molecules play well-characterized roles in each step of the process. For example, the initial rolling step of TEM is facilitated by interactions between T-cell and endothelial selectins, whereas the adhesion, intravascular crawling, and diapedesis steps of TEM are mainly regulated by chemokineand shear force-stimulated modulation of lymphocyte functionassociated antigen 1 (LFA-1, αLβ2 integrin, CD11a/CD18) and very late antigen 4 (VLA-4, α4β1 integrin, CD49d/CD29) interactions with intracellular adhesion molecule 1 ...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration

Estin

Thompson

Traxinger

et al. 2017

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

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“…Ena/Vasp can act as a bundling protein in vitro and maintains filopodium stability. The F-actin polymerase mDia on the other hand promotes filopodium elongation, which is in its turn tempered by Ena/Vasp (51).…”

Section: Fascin Guarantees Protrusion and Structural Rigidity Whereamentioning

confidence: 99%

Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia

Audenhove¹,

Denert²,

Boucherie³

et al. 2016

Journal of Biological Chemistry

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Invadopodia and filopodia are dynamic, actin-based protrusions contributing to cancer cell migration, invasion, and metastasis. The force of actin bundles is essential for their protrusive activity. The bundling protein fascin is known to play a role in both invadopodia and filopodia. As it is more and more acknowledged that functionally related proteins cooperate, it is unlikely that only fascin bundles actin in these protrusions. Another interesting candidate is L-plastin, normally expressed in hematopoietic cells, but considered a common marker of many cancer types. We identified L-plastin as a new component of invadopodia, where it contributes to degradation and invasiveness. By means of specific, high-affinity nanobodies inhibiting bundling of fascin or L-plastin, we further unraveled their cooperative mode of action. We show that the bundlers cannot compensate for each other due to strikingly different bundling characteristics: L-plastin bundles are much thinner and less tightly packed. Composite bundles adopt an intermediate phenotype, with fascin delivering the rigidity and strength for protrusive force and structural stability, whereas L-plastin accounts for the flexibility needed for elongation. Consistent with this, elevated L-plastin expression promotes elongation and reduces protrusion density in cells with relatively lower L-plastin than fascin levels.Filopodia are finger-like protrusions coordinating movement at the cell front by "sensing" extracellular stimuli (1). Invadopodia on the other hand are formed at the ventral cell side, enabling matrix degradation by localized proteolysis (2). As both actin-based protrusions contribute to migration and invasion, they are associated with cancer metastasis (3, 4), which has also been shown in vivo (5, 6).The architecture and dynamics of filopodia and invadopodia are controlled by a broad variety of actin-binding proteins (7,8). Moreover, these regulating proteins show highly similar spatial and temporal distributions in filopodia and invadopodia (9).

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“…mDia1 may be recruited by the adaptor Abi1 [58], and Mena/VASP are likely recruited by LIM domain proteins zyxin and LPP [59,60]. Interestingly, Mena/ VASP and Diaphanous formins (mDia2) were shown to cooperate in the regulation of filopodial morphology, dynamics and function [61]. Not much else is known about the interplay between the different actin polymerization factors at AJ.…”

Section: Actin Dynamics Regulation Modulementioning

confidence: 99%