aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis
Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatments. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory and anti-apoptotic activities, which is facilitated by co-receptors. We showed that aPC-activated PAR1 signals preferentially via b-arrestin-2 (b-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to enhance barrier protection. However, the mechanisms by which aPC/PAR1 promotes other cytoprotective responses are poorly understood. Here we define a novel β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. We show that PAR1 and S1PR1 co-exist in caveolin-1-rich microdomains basally and aPC markedly increases S1PR1-caveolin-1 co-association. Moreover, aPC stimulates b-arr2-dependent SphK1 activation independent of Dvl2, which is critical for S1PR1 transactivation. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete b-arr2-driven signaling pathways in caveolae..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 25. Mai Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Molinar-Inglis, Olivia [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/2021.03.27.437291 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
XBI020231504 |
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| 520 | |a Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatments. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory and anti-apoptotic activities, which is facilitated by co-receptors. We showed that aPC-activated PAR1 signals preferentially via b-arrestin-2 (b-arr2) and dishevelled-2 (Dvl2) scaffolds rather than G proteins to enhance barrier protection. However, the mechanisms by which aPC/PAR1 promotes other cytoprotective responses are poorly understood. Here we define a novel β-arr2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. We show that PAR1 and S1PR1 co-exist in caveolin-1-rich microdomains basally and aPC markedly increases S1PR1-caveolin-1 co-association. Moreover, aPC stimulates b-arr2-dependent SphK1 activation independent of Dvl2, which is critical for S1PR1 transactivation. These studies reveal that different aPC/PAR1 cytoprotective responses are mediated by discrete b-arr2-driven signaling pathways in caveolae. | ||
| 700 | 1 | |a Birch, Cierra A. |e verfasserin |4 aut | |
| 700 | 1 | |a Nicholas, Dequina |e verfasserin |4 aut | |
| 700 | 1 | |a Cisneros-Aguirre, Metzli |e verfasserin |4 aut | |
| 700 | 1 | |a Patwardhan, Anand |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Buxin |e verfasserin |4 aut | |
| 700 | 1 | |a Grimsey, Neil J. |e verfasserin |4 aut | |
| 700 | 1 | |a Gomez-Menzies, Patrick K. |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Huilan |e verfasserin |4 aut | |
| 700 | 1 | |a Coronel, Luisa J. |e verfasserin |4 aut | |
| 700 | 1 | |a Lawson, Mark A. |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Hemal H. |e verfasserin |4 aut | |
| 700 | 1 | |a Trejo, JoAnn |e verfasserin |4 aut | |
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