VASP regulates leukocyte infiltration, polarization, and vascular repair after ischemia

Laban, Hebatullah; Weigert, Andreas; Zink, Joana; Elgheznawy, Amro; Schürmann, Christoph; Günther, Lea; Malik, Randa Abdel; Bothur, Sabrina; Wingert, Susanne; Bremer, Rolf; Rieger, Michael A.; Brüne, Bernhard; Brandes, Ralf P.; Fleming, Ingrid; Benz, P.

doi:10.1083/jcb.201702048

Cited by 36 publications

(41 citation statements)

References 60 publications

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“…Direct VASP interaction with CXCR2 triggered by CXCL8 was observed in HL60 cells, which contributed to neutrophil polarization and chemotaxis [181]. Although a link to β-arrestin was not shown in that study, later it has been shown that VASP formed part of a molecular complex containing CCR2 and β-arrestin-2, and was required for CCR2 internalization [180]. Additionally, VASP is required for Rap1-mediated integrin activation, which is a prerequisite during neutrophil recruitment [182].…”

Section: Signalingmentioning

confidence: 89%

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How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways

Rajarathnam

Schnoor

Richardson

et al. 2019

Cellular Signalling

178

158

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Chemokines play crucial roles in combating microbial infection and initiating tissue repair by recruiting neutrophils in a timely and coordinated matter. In humans, no less than seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) and two receptors (CXCR1 and CXCR2) mediate neutrophil functions but in a context dependent manner. Neutrophil-activating chemokines reversibly exist as monomers and dimers, and their receptor binding triggers conformational changes that are coupled to G-protein and β-arrestin signaling pathways. G-protein signaling activates a variety of effectors including Ca 2+ channels and phospholipase C. β-arrestin serves as a multifunctional adaptor and is coupled to several signaling hubs including MAP kinase and tyrosine kinase pathways. Both G-protein and β-arrestin signaling pathways play important non-overlapping roles in neutrophil trafficking and activation. Functional studies have established many similarities but distinct differences for a given chemokine and between chemokines at the level of monomer vs. dimer, CXCR1 vs. CXCR2 activation, and Gprotein vs. β-arrestin pathways. We propose that two forms of the ligand binding two receptors and activating two signaling pathways enables fine-tuned neutrophil function compared to a single form, a single receptor, or a single pathway. We summarize the current knowledge on the molecular mechanisms by which chemokine monomers/dimers activate CXCR1/CXCR2 and how these interactions trigger G-protein/β-arrestin-coupled signaling pathways. We also discuss current challenges and knowledge gaps, and likely advances in the near future that will lead to a better understanding of the relationship between chemokine-CXCR1/CXCR2-G-protein/β-arrestin axis and neutrophil function.

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Section: Signalingmentioning

confidence: 89%

“…Vasodilator-stimulated phosphoprotein (VASP), an ABP that is important for actin polymerization, has been shown to interact with CXCR2 [180,181]. Direct VASP interaction with CXCR2 triggered by CXCL8 was observed in HL60 cells, which contributed to neutrophil polarization and chemotaxis [181].…”

Section: Signalingmentioning

confidence: 99%

How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways

Rajarathnam

Schnoor

Richardson

et al. 2019

Cellular Signalling

178

158

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“…AKAP12 is thought to be essential for the proper formation of signalling complexes with protein kinases/phosphatases, β‐arrestin and clathrin and thus for the agonist‐induced internalization and resensitization of G‐protein‐linked receptors . Ena/VASP proteins, on the contrary, interact with β 2 ‐arrestin, and have been linked with the internalization of CCR2 and the epidermal growth factor receptor, as well as the recycling of the transforming growth factor receptor . Therefore, it is tempting to speculate that the role of AKAP12 may not be limited to the integration of kinase signalling events, but AKAP12 may rather function as multi‐protein assembling machinery to coordinate actin dynamics as well as PKA‐dependent signalling at the angiogenic front.…”

Section: Discussionmentioning

confidence: 99%

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

et al. 2019

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Aim Protein kinase (PK) A anchoring protein (AKAP) 12 is a scaffolding protein that anchors PKA to compartmentalize cyclic AMP signalling. This study assessed the consequences of the downregulation or deletion of AKAP12 on endothelial cell migration and angiogenesis. Methods The consequences of siRNA‐mediated downregulation AKAP12 were studied in primary cultures of human endothelial cells as well as in endothelial cells and retinas from wild‐type versus AKAP12−/− mice. Molecular interactions were investigated using a combination of immunoprecipitation and mass spectrometry. Results AKAP12 was expressed at low levels in confluent endothelial cells but its expression was increased in actively migrating cells, where it localized to lamellipodia. In the postnatal retina, AKAP12 was expressed by actively migrating tip cells at the angiogenic front, and its deletion resulted in defective extension of the vascular plexus. In migrating endothelial cells, AKAP12 was co‐localized with the PKA type II‐α regulatory subunit as well as multiple key regulators of actin dynamics and actin filament‐based movement; including components of the Arp2/3 complex and the vasodilator‐stimulated phosphoprotein (VASP). Fitting with the evidence of a physical VASP/AKAP12/PKA complex, it was possible to demonstrate that the VEGF‐stimulated and PKA‐dependent phosphorylation of VASP was dependent on AKAP12. Indeed, AKAP12 colocalized with phospho‐Ser157 VASP at the leading edge of migrating endothelial cells. Conclusion The results suggest that compartmentalized AKAP12/PKA signalling mediates VASP phosphorylation at the leading edge of migrating endothelial cells to translate angiogenic stimuli into altered actin dynamics and cell movement.

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“…These proteins participate in multiple pathways, including complement and coagulation cascades, phagosome, and the S. aureus infection pathway. Vasodilator-stimulated phosphoprotein (Vasp) is an actin-binding protein that regulates leukocyte aggregation and polarization [29]. Vasp, neutrophil cytosolic factor 4 (Ncf4), rac family small GTPase 2 (Rac2), etc., participate in the leukocyte transendothelial migration (rno04670) pathway.…”

Section: First Category Second Category Protein Numbermentioning

confidence: 99%

Staphylococcus aureus-induced proteomic changes in the mammary tissue of rats: A TMT-based study

et al. 2020

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Staphylococcus aureus is one of the most important pathogens causing mastitis in dairy cows. The objective of this study was to establish a rat model of mastitis induced by S. aureus infection and to explore changes in the proteomes of mammary tissue in different udder states, providing a better understanding of the host immune response to S. aureus mastitis. On day 3 post-partum, 6 rats were randomly divided into two groups (n = 3), with either 100 μL of PBS (blank group) or a S. aureus suspension containing 2×10 7 CFU�mL −1 (challenge group) infused into the mammary gland duct. After 24 h of infection, the rats were sacrificed, and mammary gland tissue was collected. Tandem mass tag (TMT)-based technology was applied to compare the proteomes of healthy and mastitic mammary tissues. Compared with the control group, the challenge group had 555 proteins with significant differences in expression, of which 428 were significantly upregulated (FC>1.2 and p<0.05) and 127 were downregulated (FC>0.83 and p<0.05 or p<0.01). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that upregulated differentially significant expressed proteins (DSEPs) were associated with mainly immune responses, including integrin alpha M, inter-α-trypsin inhibitor heavy chain 4, and alpha-2-macroglobulin. This study is the first in which a rat model of S. aureusinduced mastitis was used to explore the proteins related to mastitis in dairy cows by TMT technology, providing a model for replication of dairy cow S. aureus-induced mastitis experiments.

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VASP regulates leukocyte infiltration, polarization, and vascular repair after ischemia

Cited by 36 publications

References 60 publications

How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways

How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

Staphylococcus aureus-induced proteomic changes in the mammary tissue of rats: A TMT-based study

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