RT Journal Article
SR Electronic
T1 aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete β-arrestin-2 mediated SphK1-S1PR1-Akt signaling axis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.27.437291
DO 10.1101/2021.03.27.437291
A1 Olivia Molinar-Inglis
A1 Cierra A. Birch
A1 Dequina Nicholas
A1 Metztli Cisneros-Aguirre
A1 Anand Patwardhan
A1 Buxin Chen
A1 Neil J. Grimsey
A1 Patrick K. Gomez Menzies
A1 Huilan Lin
A1 Luisa J. Coronel
A1 Mark A. Lawson
A1 Hemal. H. Patel
A1 JoAnn Trejo
YR 2021
UL http://biorxiv.org/content/early/2021/04/14/2021.03.27.437291.abstract
AB 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 β-arrestin-2 (β-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 β-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 β-arr2-driven signaling pathways in caveolae.Competing Interest StatementThe authors have declared no competing interest.