β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke

Kanki, Hideaki; Sasaki, Tsutomu; Matsumura, Shigenobu; Yokawa, Satoru; Yukami, Toshiro; Shimamura, Munehisa; Sakaguchi, Manabu; Furuno, Tadahide; Suzuki, Takahiro; Mochizuki, Hideki

doi:10.1038/s41419-019-1375-x

Cited by 15 publications

(19 citation statements)

References 72 publications

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“…While activation of PAR1 signaling by thrombin is rapid and catalyzed through coupling to heterotrimeric G proteins, APCtriggered PAR1 cytoprotective signaling is slower and mediated by β-arrestin-2-facilitated protein-protein interactions (18,40,41). Our phosphoproteomic analysis demonstrates that thrombin causes rapid increases in phosphorylation of subsets of proteins at the plasma membrane that are associated with modulation of adherens junctions.…”

Section: Discussionmentioning

confidence: 82%

Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function

Lin

Wozniak

Grimsey

et al. 2020

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

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Thrombin, a procoagulant protease, cleaves and activates protease-activated receptor-1 (PAR1) to promote inflammatory responses and endothelial dysfunction. In contrast, activated protein C (APC), an anticoagulant protease, activates PAR1 through a distinct cleavage site and promotes anti-inflammatory responses, prosurvival, and endothelial barrier stabilization. The distinct tethered ligands formed through cleavage of PAR1 by thrombin versus APC result in unique active receptor conformations that bias PAR1 signaling. Despite progress in understanding PAR1 biased signaling, the proteins and pathways utilized by thrombin versus APC signaling to induce opposing cellular functions are largely unknown. Here, we report the global phosphoproteome induced by thrombin and APC signaling in endothelial cells with the quantification of 11,266 unique phosphopeptides using multiplexed quantitative mass spectrometry. Our results reveal unique dynamic phosphoproteome profiles of thrombin and APC signaling, an enrichment of associated biological functions, including key modulators of endothelial barrier function, regulators of gene transcription, and specific kinases predicted to mediate PAR1 biased signaling. Using small interfering RNA to deplete a subset of phosphorylated proteins not previously linked to thrombin or APC signaling, a function for afadin and adducin-1 actin binding proteins in thrombin-induced endothelial barrier disruption is unveiled. Afadin depletion resulted in enhanced thrombin-promoted barrier permeability, whereas adducin-1 depletion completely ablated thrombin-induced barrier disruption without compromising p38 signaling. However, loss of adducin-1 blocked APC-induced Akt signaling. These studies define distinct thrombin and APC dynamic signaling profiles and a rich array of proteins and biological pathways that engender PAR1 biased signaling in endothelial cells.

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Section: Discussionmentioning

confidence: 82%

Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function

Lin

Wozniak

Grimsey

et al. 2020

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

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“…Despite their opposing effects, both APC and thrombin interact with PAR1 on endothelial cells [ 96 ]. A recent study demonstrated that APC activates β-arrestin-2, leading to PAR1-β-arrestin-2-MAPK 42/44 signaling that has a protective effect on endothelial function via PDGF-β [ 52 ]. APC enhanced tube-like capillary formation, migration, and transepithelial electrical resistance (TEER) while reducing permeability in bovine brain microvasculature endothelial cells [ 52 ].…”

Section: β-Arrestin-mediated Gpcr Signaling In the Endotheliummentioning

confidence: 99%

“…A recent study demonstrated that APC activates β-arrestin-2, leading to PAR1-β-arrestin-2-MAPK 42/44 signaling that has a protective effect on endothelial function via PDGF-β [ 52 ]. APC enhanced tube-like capillary formation, migration, and transepithelial electrical resistance (TEER) while reducing permeability in bovine brain microvasculature endothelial cells [ 52 ]. In contrast, thrombin decreased expression of occludin, claudin-5, and ZO-1 and rapidly induced vascular permeability.…”

Section: β-Arrestin-mediated Gpcr Signaling In the Endotheliummentioning

confidence: 99%

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Beta-Arrestins and Receptor Signaling in the Vascular Endothelium

et al. 2020

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The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.

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“…PDGFb receptor transactivation may also play a role in BBB function. PDGFb receptor signaling protects endothelial cell function and BBB integrity after b-arrestin activation subsequent to protease-activated receptor 1 [93] . Thus, in addition to GPCR-PDGFb receptor transactivating and directly impacting neuronal health, transactivation or indirect activation of PDGF signaling may also impact BBB integrity in the context of stroke or other neurological diseases.…”

Section: Neuroprotective Effects Of Pdgf Receptor Transactivationmentioning

confidence: 99%

Neuroprotective effects of direct activation and transactivation of PDGFβ receptors

Vasefi¹,

Beazely²

2020

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Platelet-derived growth factor (PDGF) receptors are expressed throughout the body, including the central nervous system (CNS). Although the physiological role of PDGF receptors in the developed CNS is not fully characterized, PDGF signaling appears to provide neuroprotective effects against several neuronal insults. One of the bestcharacterized neuroprotective effects of PDGF type-b receptors is against human immunodeficiency virus (HIV) protein-induced neurotoxicity, with potential physiological relevance to HAD. PDGFb receptors are also neuroprotective against glutamate excitotoxicity, which is associated with both stroke and neurodegenerative diseases, including Alzheimer's disease. The neuroprotective effects of PDGFb receptors occur both via direct activation by ligand (PDGF-BB), as well as by PDGFb receptors activated downstream of G protein-coupled receptor signaling. In addition to the involvement of PDGF signaling in various pathologies and potential therapies, there is also an emerging body of evidence that PDGF may serve as a biomarker for neurological or psychiatric diseases.

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β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke

Cited by 15 publications

References 72 publications

Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function

Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function

Beta-Arrestins and Receptor Signaling in the Vascular Endothelium

Neuroprotective effects of direct activation and transactivation of PDGFβ receptors

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