VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis

Neel, Nicole F.; Barzik, Melanie; Raman, Dayanidhi; Sobolik-Delmaire, Tammy; Sai, Jiqing; Ham, Amy Joan L.; Mernaugh, Raymond L.; Gertler, Frank B.; Richmond, Ann

doi:10.1242/jcs.039057

Cited by 54 publications

(55 citation statements)

References 47 publications

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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%

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%

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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“…However, cell-type-specific regulation of Ena/VASP proteins might exist because the phosphorylation status of S239 modulates VASP localization in renal epithelial cells in NO-dependent signaling pathways (Lindsay et al, 2007). Importantly, phosphorylation at S239 and T278 has significant effects on VASP interaction with G-and F-actin (Barzik et al, 2005;Harbeck et al, 2000) as well as on the ability of VASP to bind the chemotactic receptor CXCR2 (Neel et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Differential VASP phosphorylation controls remodeling of the actin cytoskeleton

Benz

Blume

Seifert

et al. 2009

Journal of Cell Science

156

234

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Proteins of the Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family link signal transduction pathways to actin cytoskeleton dynamics. VASP is substrate of cAMP-dependent, cGMP-dependent and AMP-activated protein kinases that primarily phosphorylate the sites S157, S239 and T278, respectively. Here, we systematically analyzed functions of VASP phosphorylation patterns for actin assembly and subcellular targeting in vivo and compared the phosphorylation effects of Ena/VASP family members. Methods used were the reconstitution of VASP-null cells with `locked' phosphomimetic VASP mutants, actin polymerization of VASP mutants in vitro and in living cells, site-specific kinase-mediated VASP phosphorylation, and analysis of the endogenous protein with phosphorylation-status-specific antibodies. Phosphorylation at S157 influenced VASP localization, but had a minor impact on F-actin assembly. Phosphorylation of the S157-equivalent site in the Ena/VASP family members Mena and EVL had no effect on the ratio of cellular F-actin to G-actin. By contrast, VASP phosphorylation at S239 (and the equivalent site in Mena) or T278 impaired VASP-driven actin filament formation. The data show that VASP functions are precisely regulated by differential phosphorylation and provide new insights into cytoskeletal control by serine/threonine kinase-dependent signaling pathways.

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“…10 In fact, chemokine receptors signaling could be regulated by several adaptors that mediate the internalization and signal transduction by forming a dynamic bond with spatial and temporal plasticity (chemosynapse). [20][21][22] Interestingly, non-signaling-chemokine receptors (decoy receptors) were described which do not elicit conventional signaling responses, but display inflammatory and immunomodulatory effects. Until now, 3 decoy receptors were described, chemokine decoy receptor (D6), Duffy antigen receptor for chemokines (DARC) and chemocentryx decoy receptor (CCX CKR).…”

Section: Chemokines and Other Chemoattractants At Early Pregnancymentioning

confidence: 99%

Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation

Ramhorst

Grasso

Paparini

et al. 2016

Cell Adhesion & Migration

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Chemokine network is central to the innate and adaptive immunity and entails a variety of proteins and membrane receptors that control physiological processes such as wound healing, angiogenesis, embryo growth and development. During early pregnancy, the chemokine network coordinates not only the recruitment of different leukocyte populations to generate the maternalplacental interface, but also constitutes an additional checkpoint for tissue homeostasis maintenance. The normal switch from a pro-inflammatory to an anti-inflammatory predominant microenvironment characteristic of the post-implantation stage requires redundant immune tolerance circuits triggered by key master regulators. In this review we will focus on the recruitment and conditioning of maternal immune cells to the uterus at the early implantation period with special interest on high plasticity macrophages and dendritic cells and their ability to induce regulatory T cells. We will also point to putative immunomodulatory polypeptides involved in immune homeostasis maintenance at the maternal-placental interface.

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VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis

Abstract: SummaryVASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis

Cited by 54 publications

References 47 publications

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

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

Differential VASP phosphorylation controls remodeling of the actin cytoskeleton

Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation

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